CA2570197C - Nk1 antagonists - Google Patents

Nk1 antagonists Download PDF

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Publication number
CA2570197C
CA2570197C CA2570197A CA2570197A CA2570197C CA 2570197 C CA2570197 C CA 2570197C CA 2570197 A CA2570197 A CA 2570197A CA 2570197 A CA2570197 A CA 2570197A CA 2570197 C CA2570197 C CA 2570197C
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CA2570197A
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CA2570197A1 (en
Inventor
Anandan Palani
Xianhai Huang
Dong Xiao
Sunil Paliwal
Hon-Chung Tsui
Michelle Laci Wrobleski
Ashwin U. Rao
Cheng Wang
Sapna S. Shah
Neng-Yang Shih
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Opko Health Inc
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Opko Health Inc
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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Abstract

A compound having the general structure shown in Formula I:
(see formula I) or pharmaceutically acceptable salts and/or solvates thereof are useful in treating diseases or conditions mediated by NK1 receptors, for example various physiological disorders, symptoms or diseases, including emesis, depression, anxiety and cough.

Description

NKi ANTAGONISTS
FIELD OF THE INVENTION
The present invention relates to novel neurokinin-1 (NKi or NK-1) receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds, to treat NKi receptor mediated diseases and conditions, including, for example, emesis, depression, anxiety and cough.
BACKGROUND OF THE INVENTION
Tachykinins are peptide ligands for neurokinin receptors. Neurokinin receptors, such as NKI, NK2 and NK3, are involved in a variety of biological processes. They can be found in a mammal's nervous and circulatory systems, as well as in peripheral tissues. Consequently, the modulation of these types of receptors has been studied to potentially treat or prevent various mammalian disease states. For instance, NKi receptors have been reported to be involved in microvascular leakage and mucus secretion.
Representative types of neurokinin receptor antagonists and the disorders that can be treated with them include, for example, sleep, pain, migraine, emesis, nociception ancf inflammation; see, for example, U.S. 6,329,401, U.S.
5,760,018, U.S. 5,620,989, WO 95/19344, WO 94/13639, WO 94/10165, Wu et al., Tetrahedron, 56, 6279-6290 (2000), Rombouts et al., Tetrahedron, 59, 4721-4731 (2003), and Rogiers et al., Tetrahedron, 57,_8971-8981 (2001).
It would be beneficial to provide a WI antagonist that is potent, selective, and possesses beneficial therapeutic and pharmacological properties, and good metabolic stability. It would further be beneficial to provide a NKi antagonist that is effective for treating a variety of physiological disorders, symptoms and diseases, while minimizing side effects. This invention provides such NKi antagonists.

SUMMARY OF THE INVENTION
In one embodiment, the present invention is directed to a compound of Formula I:

Ar2 NJ) Arl _________________________________ 0 R3 (I) or pharmaceutically acceptable salts and/or solvates thereof, wherein:
R1 and R2 are each independently selected from the group consisting of H, alkyl, haloalkyl, alkyl substituted with one or more hydroxyl groups, -CN, alkynyl, -N(R6)2, -N (R6)-S(02)-alkyl, -N (R6)-C(0)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(0)-alkyl, -C(=N-OR5)-alkyl, -C(0)-N(R9)2, -C(0)-0-alkyl, -alkylene-C(0)-alkyl, -alkylene-C(0)-0-alkyl, -alkylene-C(0)-N(R9)2, HN \
0 L.
0 \ 0 \
, .r'P-, and JN-r`-', )m with the proviso that at least one of R1 and R2 is ¨CN, avAL , z- ow HN

Or\l/
\ 0 \
W is =C(R8)- or =N-;
X is ¨C(0)- or -S(02)-;
Y is selected from the group consisting of ¨CH2-, -0-, and -N(R6)-C(0)-, with the proviso that:
(a) the nitrogen atom of -N(R6)-C(0)- is bonded to X, and =
X\ (2 )n, (b) if R1 and/or R2 is 01-i-L and Y is ¨0-, X is not -S(02)-;
is ¨C(R7)2-, ¨N(R8)-, or ¨0-;
R3 is selected from the group consisting of H, -CH2OR5, and alkyl;
R4 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, acyl, aroyl, alkylsulfonyl, and arylsulfonyl;
R5 is H or alkyl;
R6 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl;
each R7 is independently H or alkyl; or each R7, together with the ring carbon to which they are shown attached, form a cycloalkylene ring;
R8 is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -N(R6)2, -N(R6)-S(02)-alkyl, -N (R6)-S(02)-aryl, -N(R6)-C(0)-alkyl, -N(R6)-C(0)-aryl, alkylene-O-alkyl, and -CN;
R9 is selected from the group consisting of H, alkyl, and aryl, or each R9, together with the nitrogen to which they are shown attached, form a heterocycloalkyl ring;
Arl and Ar2 are each independently selected from the group consisting of unsubstituted aryl and aryl substituted with 0 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -CN, -OH, and -NO2;
n is 0, 1, or 2; and m is 1, 2, or 3.
- In another embodiment,-the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable carrier.
In another embodiment, the present invention is directed to a kit comprising two or more containers in a single package, wherein each container in the package comprises a pharmaceutical composition. At least one container of the package comprises an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof in a pharmaceutically acceptable carrier, and at least one other container of the package comprises another therapeutic agent in a pharmaceutically acceptable carrier. The pharmaceutical compositions of the kit may be used in combination.
In another embodiment, the present invention is directed to a method for affecting an NKi receptor in a patient. The method comprises administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
In another embodiment, the present invention is directed to a method for treating an Nici receptor mediated condition or disease (i.e., a disease associated with an NKi receptor, or a disease involving an NIKi receptor in part of the disease process) in a patient in need of such treatment. The method comprises administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
In a first embodiment, the present invention is directed to a compound of Formula I, or a solvate and/or salt thereof, as described herein.
In yet another embodiment, the compounds of Formula I have the following structure IA:

Ar2 n Arlir (IA) In yet another embodiment of the compounds of Formula I, R3 is alkyl;
R4 is H;
Arl is phenyl;
Ar2 is a phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1_6 alkyl, C1_6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -CN, and -NO2; and n is 1.
In yet another embodiment of the compounds of Formula I, R3 is alkyl;
R4 is H;
Arl is phenyl;
Ar2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1_6 alkyl, C1_6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -CN, and -NO2; and n is 1.
In yet another embodiment, the compounds of Formula I have the following structure IA:
Dl \Fe Ar2 Arl R3 (IA) R3 is C1-6 alkyl;
R4 is H;
Arl is phenyl;
Ar2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1_6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -CN, and -NO2; and n is 1.
In yet another embodiment, the compounds of Formula I have the following structure IA:
R.1 ,R2 Ar2 )n Arl (IA) wherein R1 and R2 are each independently selected from the group consisting of H, -CH3, -CH2CH2CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2CH2OH, -CH2CH(OH)CH3, -CH2C(OH)(CH3)2, -CN, -CH2CN , -NH2, -NH-S(02)-CH3, -NH-C(0)-NH2, -CH2OCH3, -C(0)-CH3 , -C(0)-CH2CH3, -C(=N-OH)-CH3, -C(=N-OH)-CH2CH3, -C(=N-OCH3)-CH3, -C(0)-NH2, -C(0)-NH(CH3), -C(0)-0-CH3 or -C(0)-0-CH2CH3, -CH2-C(0)-CH3, -CH2-C(0)0-CH3, -CH2-C(0)0-CH2CH3, , c2õ-N9 ¨N? `22.¨NO0 c 02S\\ 11 -CH2C(0)-NH(CH2CH3), -CH2C(0)-NH2, 0, 0 , 0 , OH

caz¨N. c227.-N VN\r,NH (.22--NNH (22.-- m"\NH

i, ii ., . , 0 0 , 0 , , 0.3 .....õs_cH3 cN )=---N>---7---N N_--,N f-----N
y"e2--N 6 `22¨N il\ili (2,2.--N /1\ai (22.¨N, it\ll.i `22¨N cH3 y y y Ycc,_,3 )\---N
N
'az¨N 0 /

----("z:=N
1 HN )) 0 , ,P-ru,2,,a---Ni \- N, and =A;
R3 is -CH3; , R4 is H;
Arl is phenyl;
Ar2 is phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C1_6 alkyl, C1_6 alkoxy, C1 -5 haloalkyl, C1-6 haloalkoxy, -CN, and -NO2; and n is I.
In yet another embodiment of the compounds of Formula I, Arl is unsubstituted phenyl or phenyl substituted with 1 to 3 substituents selected from the group consisting of CI, F, Br, -OH, C1-6 alkyl, C1_6 alkoxy, C1-6 haloalkyl, Ci haloalkoxy, -CN, and -NO2.
In yet another embodiment of the compounds of Formula I, Ari is unsubstituted phenyl.
In yet another embodiment of the compounds of Formula I, Ar2 is unsubstituted phenyl or phenyl substituted with 1 to 3 substituents selected from the group consisting of CI, F, Br, -OH, C1-6 alkyl, C1_6 alkoxy, C1-6 haloalkyl, C1_6 haloalkoxy, -CN, and -NO2.
In yet another embodiment of the compounds of Formula I, Ar2 is substituted phenyl.
In yet another embodiment of the compounds of Formula I, Ar2 is 3,5-bis(trifluoromethyl)phenyl.
In yet another embodiment of the compounds of Formula I, R1 is H.
In yet another embodiment of the compounds of Formula I, R1 is a C1.6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.
In yet another embodiment of the compounds of Formula I, R1 is a haloalkyl, for example -CH2CI, -CH2F, -CHCl2, -CHF2, -CF3.
In yet another embodiment of the compounds of Formula I, R1 is a C2-6 alkynyl, for example -CEC-H, -CC-CH3, -CC-CH2CH3, etc.
In yet another embodiment of the compounds of Formula I, R1 is a C1_6 alkyl substituted with one or more hydroxy groups, for example ¨CH2OH, -CH2CH2OH, -CH2CH(OH)CH3, or -CH2C(OH)(CH3)2.
In yet another embodiment of the compounds of Formula I, R1 is ¨CN
or -C1_6 alkylene-CN, for example ¨CH2CN.
another_embodiment of the compounds of Formula I, R1 is ¨NH2.
In yet another embodiment of the compounds of Formula I, R1 is -NH-S(02)-Ci_6 alkyl, for example -NH-S(02)-CH3.
In yet another embodiment of the compounds of Formula I, R1 is -NH-C(0)-N H2.
In yet another embodiment of the compounds of Formula I, R1 is -C1-6 alkylene-O-C1_6 alkyl, for example -CH2OCH3.
In yet another embodiment of the compounds of Formula I, R1 is -C(0)-C1.6 alkyl, for example ¨C(0)-CH3 or ¨C(0)-CH2CH3.
In yet another embodiment of the compounds of Formula I, R1 is -C(=N-OH)-Ci_s alkyl or -C(=N-0-C1.6 alkyl)-C1_6 alkyl, for example -C(=N-OH)-CH3, -C(=N-OH)-CH2CH3, or -C(=N-OCH3)-CH3.
In yet another embodiment of the compounds of Formula I, R1 is -C(0)-NH(C1_6 alkyl), -C(0)-N(C1_6 alky1)2, -C(0)-NH(C6_10 aryl), -C(0)-N(C6-ary1)2, -C(0)-N(C1_6 alkyl)( C6_10 aryl), or ¨C(0)-NH2, for example ¨C(0)-NH2 or ¨C(0)-NH(CH3).
In yet another embodiment of the compounds of Formula I, R1 is -C(0)-0-C1_6 alkyl, for example -C(0)-0-CH3 or -C(0)-0-CH2CH3.
In yet another embodiment of the compounds of Formula I, R1 is -C1-6 alkylene-C(0)-C6 alkyl, for example ¨CH2-C(0)-CH3.
In yet another embodiment of the compounds of Formula I, R1 is -C1-6 alkylene-C(0)-0-C1_6 alkyl, for example ¨CH2-C(0)0-CH3 or -CH2-C(0)0-CH2CH3.
In yet another embodiment of the compounds of Formula I, R1 is ¨C1-6 alkylene-C(0)-NH2, ¨C1_6 alkylene-C(0)-NH(C1_6 alkyl), ¨C1-6 alkylene-C(0)-N(C1_6 alky1)2, ¨C1.6 alkylene-C(0)-NH(C6_10 aryl),¨C16 alkylene-C(0)-N(C6_10 ary1)2, or ¨C1_6 alkylene-C(0)-N(C1_6 alkyl)(C6_10 aryl), for example ¨CH2C(0)-NH(CH2CH3) or ¨CH2C(0)-NH2.
In yet another embodiment of the compounds of Formula I, R1 is one of:
r"--\
"22--Ny c (OH OCH3 NH rz--N c¨N
ni "?..2.---N\ )4H "22---N "22----N
HN
fl\JH (72--N \jiq (72¨Nyv cH3 )\--N
HN
0 , \, or In yet another embodiment of the compounds of Formula I, R2 is H.
In yet another embodiment of the compounds of Formula I, R2 is a C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.
In yet another embodiment of the compounds of Formula I, R2 is a C1-6 haloalkyl, for example -CH2CI, -CH2F, -CHCl2, -CHF2, -CF3.
In yet another embodiment of the compounds of Formula I, R2 is a C2-6 alkynyl, for example -CEC-H, -CC-CH3, -CEC-CH2CH3, etc.
In yet another embodiment of the compounds of Formula I, R2 is a C1-6 alkyl substituted with one or more hydroxy groups, for example -CH2OH, -CH2CH2OH, -CH2CH(OH)CH3, or -CH2C(OH)(CH3)2.
In yet another embodiment of the compounds of Formula I, R2 is -CN
or -Ci_s alkylene-CN, for example -CH2CN or -C(CH3)2CN.
In yet another embodiment of the compounds of Formula I, R2 is -C3-6 cycloalkylene-CNTfor-example--/- - In yet another embodiment of the compounds of Formula I, R2 is -NH2.
In yet another embodiment of the compounds of Formula I, R2 is NH-S(02)-C1.6 alkyl, -N(C1..6 alkyl)-S(02)-C1_6 alkyl or -N(C6..10 aryl)-S(02)-alkyl for example -NH-S(02)-CH3.
In yet another embodiment of the compounds of Formula I, R2 is -NH-C(0)-NH2.
In yet another embodiment of the compounds of Formula I, R2 is -Ci_6 alkylene-O-Ci_6 alkyl, for example -CH2OCH3.
In yet another embodiment of the compounds of Formula I, R2 is -C(0)-C1_6 alkyl, for example ¨C(0)-CH3 or ¨C(0)-CH2CH3.
In yet another embodiment of the compounds of Formula I, R2 is -C(=N-OH)-Ci_6,alkyl or -C(=N-0-C1_6 alkyl)-C1_6 alkyl, for example -C(=N-OH)-CH3, -C(=N-OH)-CH2CH3, or -C(=N-OCH3)-CH3.
In yet another embodiment of the compounds of Formula I, R2 is -C(0)-NH(C1_6 alkyl), -C(0)-N(C1_6 alky1)2, -C(0)-NH(C6_10 aryl), -C(0)-N(C6-ary1)2, -C(0)-N(C1_6 alkyl)( C6-10 aryl), or ¨C(0)-NH2, for example ¨C(0)-NF12 or ¨C(0)-NH(CH3).
In yet another embodiment of the compounds of Formula I, R2 is -C(0)-0-Ci_6 alkyl, for example -C(0)-0-CH3 or -C(0)-0-CH2CH3.
In yet another embodiment of the compounds of Formula I, R2 is -C1-6 alkylene-C(0)-C1_6 alkyl, for example ¨CH2-C(0)-CH3.
In yet another embodiment of the compounds of Formula 1, R2 is -C1-6 alkylene-C(0)-0-6 alkyl, for example ¨CH2-C(0)0-CH3 or -CH2-C(0)0-CH2CH3.
In yet another embodiment of the compounds of Formula I, R2 is ¨C1-6 alkylene-C(0)-NH2, ¨C1_6 alkylene-C(0)-NH(C1_6 alkyl), ¨C1-6 alkylene-C(0)-N(C1_6 alky1)2, ¨C1.6 alkylene-C(0)-NH(C6.10 aryl),¨C1-6 alkylene-C(0)-N(C6_10 ary1)2, or ¨C1_6 alkylene-C(0)-N(C1.6 alkyl)(C6-10 aryl), for example ¨CH2C(0)-NH(CH2CH3) or ¨CH2C(0)-NF12.
In yet another embodiment of the compounds of Formula I, R2 is one of:
-2 ,s 0* \\

mr-fi ill (.7 5z11 carN\JH

j0 HN
NN N rN
cetz¨N\11\1H (22.--N\.)1H ys--CH3 (2z---Nyv lsc>

cH3 )\--N
N
õN 01 0 , or In yet another embodiment of the compounds of Formula I, R3 is a C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.
In yet another embodiment of the compounds of Formula I, R4 is H.
In yet another embodiment of the compounds of Formula I, R4 is C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.
In yet another embodiment of the compounds of Formula I, R4 is C3.6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In yet another embodiment of the compounds of Formula I, R4 is C3-6 heterocycloalkyl, for example pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, azetidinyl, morpholinyl, piperazinyl, or piperidinyl.
In yet another embodiment of the compounds of Formula I, R4 is C5-12 heteroaryl, for example benzimidazolyl, benzofuranyl, benzothiophenyl, -furaffY1,--Mo1yl, i oquinoly1; pyrazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinoxalinyl, quinazolinyl, thiophenyl, isoxazolyl, triazolyl, thiazolyl, or thiadiazolyl.
In yet another embodiment of the compounds of Formula I, R4 is C6-10 aryl, for example phenyl or naphthyl.
In yet another embodiment of the compounds of Formula I, R4 is C1-6 acyl, for example ¨C(0)CH3, -C(0)CH2CH3, -C(0)CH2CH2CH3, -C(0)CH(CH3)2, -C(0)C(CH3)3, or -C(0)CH2CH(C1-13)2.
In yet another embodiment of the compounds of Formula I, R4 is C6-10 aroyl, for example benzoyl or naphthoyl.
In yet another embodiment of the compounds of Formula I, R4 is C1-3 alkylsulfonyl, for example ¨S(02)CH3 or ¨S(02)CH2CH3.
In yet another embodiment of the compounds of Formula I, R4 is C6_10 arylsulfonyl, for example ¨S(02)-phenyl or ¨S(02)-naphthyl.
In yet another embodiment of the compounds of Formula I, R5 is H.
In yet another embodiment of the compounds of Formula I, R5 is C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.
In yet another embodiment of the compounds of Formula I, R6 is H.
In yet another embodiment of the compounds of Formula I, R6 is C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.
In yet another embodiment of the compounds of Formula I, R6 is C3_6 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In yet another embodiment of the compounds of Formula I, R6 is C6-10 aryl, for example phenyl or naphthyl.
In yet another embodiment of the compounds of Formula I, R7 is H.
In yet another embodiment of the compounds of Formula I, R7 is C1_6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.
In yet another embodiment of the compounds of Formula I, each R7, together with the carbon atom to which they are shown attached, form a C3-6 caa cSS(22. cS5 c72.
cS5 cSS
cycloalkyl ring, for example -2C , , ö, or .
In yet another embodiment of the compounds of Formula I, R8 is H.
In yet another embodiment of the compounds of Formula I, R5 is C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, and n-hexyl.
In yet another embodiment of the compounds of Formula I, R8 is -NH-S(02)-C1-6 alkyl, -N (C16 alkyl)-S(02)-C1.6 alkyl or ¨N(C6_10 aryl)-S(02)-alkyl for example -NH-S(02)-CH3.
In yet another embodiment of the compounds of Formula I, R8 is -NH-S(02)-C6_10 aryl, -N(C1.6 alkyl)-S(02)-C610 aryl or ¨N(C6_10 aryl)-S(02)-C6_10 aryl, for example -NH-S(02)-phenyl or -NH-S(02)-4-methylphenyl.
In yet another embodiment of the compounds of Formula I, R8 is -NH-C(0)-C1.6 alkyl, -N(C1_6 alkyl)-C(0)-Ci_6 alkyl or ¨N(C6_10 aryl)-C(0)-C1-alkyl for example -NH-S(02)-CH3.
In yet another embodiment of the compounds of Formula I, R8 is -NH-C(0)-C6_10 aryl, -N(C1_6 alkyl)-C(0)-C6_10 aryl or ¨N(C6_10 aryl)-C(0)-C6.10 aryl, for example -NH-C(0)-phenyl or -NH-C(0)-4-methylphenyl.
In yet another embodiment of the compounds of Formula I, R8 is -C1_6 alkylene-O-C1.6 alkyl , for example -CH2OCH3.
In yet another embodiment of the compounds of Formula I, R8 is a C1-6 alkyl substituted with one or more hydroxy groups, for example ¨CH2OH, -CH2CH2OH, -CH2CH(OH)CH3, or -CH2C(OH)(CI-13)2.
In yet another embodiment of the compounds of Formula I, R8 is ¨CN.
In yet another embodiment of the compounds of Formula I, R8 is ¨NH2, -N(C1.6 alky1)2, -NH(Ci..6 alkyl), -N(C6_10 ary1)2, -NH(C6_10 aryl), -N(C3-6 cycloalky1)2, -NH(C3.6 cycloalkyl), -N(C1.6 alkyl)(C6-10 aryl), -N(C1-6 cycloalkyl)(C6_10 aryl), or -N(C1_6 cycloalkyl)(Ci_6 alkyl).
In yet another embodiment of the compounds of Formula I, R9 is H.
In_yet_another_emb_odiment of_the_comp_ouncls_of Formula I, R9 is C1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, or n-hexyl.
In yet another embodiment of the compounds of Formula I, R9 is C6-10 aryl, for example phenyl or nap hthyl.
In yet another embodiment of the compounds of Formula I, each R9 together with the nitrogen atom to which they are shown attached, form a C1-6 heterocycloalkyl ring. For example ¨N(R9)2 forms one of -----1\11 O.
, or In yet another embodiment of the compounds of Formula I, X is ¨C(0)-.
In yet another embodiment of the compounds of Formula I, X is -S(02)-.
In yet another embodiment of the compounds of Formula I, Y is ¨CFI2-.
In yet another embodiment of the compounds of Formula I, Y is ¨0-.
In yet another embodiment of the compounds of Formula I, Y is -N(H)-C(0)-, -N(C1.6 alkyl)-C(0)-, or -N(C6_10 aryl)-C(0)-, for example -N(H)-C(0)-, -N(CH3)-C(0)-, or -N(phenyI)-C(0)-.
In yet another embodiment of the compounds of Formula I, Z is ¨CH2-.
In yet another embodiment of the compounds of Formula I, Z is ¨C(Ci-e alky1)2 or ¨CH(C1_6 alkyl), for example ¨C(CH3)2- or ¨CH(CH3)-=
In yet another embodiment of the compounds of Formula I, Z is ¨NH-.
In yet another embodiment of the compounds of Formula I, Z is ¨N(C1.6 alkyl)-, for example ¨N(CH3)- or ¨N(CH2CF13)-=
In yet another embodiment of the compounds of Formula I, Z is -N(C6..
10 aryl)-, for example ¨N(phenyI)- or ¨N(naphthyl)-.
In yet another embodiment of the compounds of Formula I, Z is ¨0-.
In yet another embodiment of the compounds of Formula I, n is 0.
In yet another embodiment of the compounds of Formula I, n is 1.
In yet another embodiment of the compounds of Formula I, n is 2.
In still yet another embodiment, the compounds of Formula I have the following structure IB:
D 1 .102 " C F3 HN
'= 0 =

=25 (IB) =
wherein each of R1 and R2 are as shown in the following Table I:
Compound R1 R2 n -CN

Y

1= IN OH

ii OH

(2-2.-- N \, N H rS"\-CCH3 1:=-N
5GerN i \.,- N -CH2CN
1.-=--N
6 -CH3 t 7 -CN m I
"22---.,\.;õõN
f"--:---N
8 -C(0)-0-CH3 i 9 (72.--q -CN

r---N

-- -C(0)-NH2 rzz NII
11 c2rN \.,. NH -CH2C(OH)(CH3)2 ll r---z-N

(72¨N\N
Compound R1 _____________ i-2 fN

(22¨N N
(22¨"NyNH
-CH2-NH-S(02)-CH3 16 (22---Ny NH ¨CH2C(0)-NH(CH2CH3) car Ny NH
-CH2-C(0)0-CH2CH3 ---18 (22.--Ny NH -C(=N-OH)-CH2CH3 c2a¨N\NH
-C(0)-CH2CH3 7-1o carN\r,NH

21 carN\e,NH ¨C(0)-NH(CH3) 52.-22 ¨C(0)-NH(CH3) N \r,NH

23 caa¨NH ¨CH2OH

Compound R.1 R2 7=1\11 24 car N \.NH

25 carN\,, NH

26 c1/4"-N.NH
-cH2ocH3 27 -CH2OCH3 (2z¨ N

rz---29 c-1--rN\f,NH
-CH2C(0)-NH2 30 carN\c-NH
-CH2-C(0)-CH3 tar-N\NH

-CH2-C(0)0-CH3 -CN
IZY

33 car- N?
-CN

Compound R1 R2 36 -NH-S(02)-CH3 -CN
37 -CN -NH-S(02)-CH3 _cH2.

39 -CN ¨NH2 40 ¨NH2 -CN
41 -NH-C(0)-NH2 -CN
caz--N 11\ffi -CN

OH

car " NH

OCH3 ____________________________________________________ 45 c-N
"tz¨N\NH

Compound R1 R2 ¨N
NH
o --is ¨CH3 HN

L2a--N H

0,//
-;,s-CH3 HN

NH

49 m 50 H Laa--"\NH

51 `22.¨N
-C(0)-N H2 1\11 52 (2.2.¨NNNH -C(=N-OCH3)-CH3 Compound R1 R2 53 (?-27¨N.NH
I/ ¨C(0)-CH3 54 carN\e,NH
-C(=N-OH)-CH3 55 Laa,--NNH
-c(0)0cH3 56 c22¨N

eizzl 58 Lar"-Nr"lEi -c(=N-ocH3)-cH2cH3 59 -NHC(0)CH3 ORN/
jf N¨N
, 60 c2z¨N f\n_i NI:-_¨_N
61 (2a¨N1 /11H

In still an additional embodiment, the present invention is directed to a method of treating a disease (or disorder or condition) in a patient in need of such treatment, wherein the disease is selected from the group consisting of:
(1) respiratory diseases (e.g., chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (e.g., arthritis and psoriasis), (3) skin disorders (e.g., atopic dermatitis and contact dermatitis), (4) ophthalmalogical disorders (e.g., retinitis, ocular hypertension and cataracts), (5) central nervous system conditions, such as depressions (e.g., neurotic depression), anxieties (e.g., general anxiety, social anxiety and panic anxiety disorders), phobias (e.g., social phobia), and bipolar disorder, (6) addictions (e.g., alcohol dependence and psychoactive substance abuse), (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) Alzheimer's disease, (12) AIDS related dementia, (13) Towne's disease, (14) stress related disorders (e.g., post traumatic stress disorder), (15) obsessive/compulsive disorders, (16) eating disorders (e.g., bulimia, anorexia nervosa and binge eating), (17) sleep disorders, (18) mania, (19) premenstrual syndrome, (20) gastrointestinal disorders (e.g., irritable bowel syndrome, Crohn's disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (e.g., pulmonary fibrosis), (23) obesity, (24) Type II
diabetes, (25) pain related disorders (e.g., headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), (26) bladder and genitourinary disorders (e.g., interstitial cystitis and urinary incontinence), (27) emesis (e.g., chemotherapy-induced (e.g., induced by cisplatin, doxorubicin, and taxane), radiation-induced, motion sickness, ethanol-induced, and post operative nausea and vomiting), and (28) nausea, comprising administering to the patient an effective amount of at least one (e.g., one) compound of Formula I or a pharmaceutically acceptable salt and/orsolvate thereof.
In still an additional embodiment, the present invention is directed to a method of treating a disease (or disorder or condition) in a patient in need of such treatment, wherein the disease is selected from the group consisting of:
respiratory diseases (e.g., cough), depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorders, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related disorders (e.g., headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), bladder disorders, genitourinary disorders, emesis and nausea, comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
In still an additional embodiment, the present invention also is directed to a method of treating a disease (or disorder or condition) wherein there is microvascular leakage and mucus secretion in a patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
In still an additional embodiment, the present invention also is directed to a method of treating asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
In still an additional embodiment, the present invention also is directed to a method of treating emesis, depression, anxiety and cough in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
In still an additional embodiment, the present invention also is directed to a method for antagonizing an effect of a Substance P at a neurokinin-1 receptor site in a patient in need of such treatment, comprising administering to the patient at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
In still an additional embodiment, the present invention also is directed to a method for the blockade of NKi receptors in a patient in need of such treatment, comprising administering to the patient at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof.
In still an additional embodiment, the present invention also is directed to a method for treating depression and/or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of one or more anti-depressant agents and/or one or more anti-anxiety agents.
In still an additional embodiment, the present invention also is directed to a method of treating an Nki receptor mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors ("SSRls").
In still an additional embodiment, the present invention also is directed to a method of treating depression and/or anxiety in a patient in need of such treatment comprising administering to the patient an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of one or more selective serotonin reuptake inhibitors.
In yet an additional embodiment, the present invention also is directed to a method of treating an NKi receptor mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: other types of Nki receptor antagonists (e.g., NKi receptor antagonists other than those according to Formula I of the present invention), prostanoids, Hi receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, ___ melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA
antagonists, renin inhibitors, serotonin 5-NT3 receptor antagonists (e.g., ondansetron), serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids (e.g., dexamethasone), rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein 5.
In yet an additional embodiment, the invention also is directed to a method for treating an Nki mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with at least one therapeutic agent selected from the group consisting of: prostanoids, such as prostaglandin El; a-adrenergic agonists, such as phentolamine mesylate;
dopamine receptor agonists, such as apomorphine; angiotensin II
antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA
antagonists, such as bosentan and ABT-627; serotonin 5-HT3 receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone.
In yet an additional embodiment, the invention also is directed to a method for treating an Nki mediated disease (or disorder or condition) in a patient in need of such treatment comprising administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in combination with an effective amount of at least one therapeutic agent selected from the group consisting of: other types of NKi receptor antagonists, SSR1s, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multi-drug resistance protein 5.
In yet an additional embodiment, the invention also is directed to a method for treating emesis, nausea and/or vomiting in a patient in need of such treatment comprising administering to the patient an effective amount of -----at-least-one-compoundaf-Formula-1-or-a-pharmaceutically-acceptable salt and/or solvate thereof, in combination with an effective amount of at least one serotonin 5-HT3 receptor antagonist (e.g., ondansetron) and/or at least one glucocorticoid (e.g., dexamethasone).
In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an Nki receptor mediated disease (or disorder or condition), wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising another therapeutic agent in a pharmaceutically acceptable carrier, the therapeutic agent being selected from the group consisting of: SSR1s, other types of NK-i receptor antagonists, prostanoids, H1 receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids, rho kinase inhibitors, potassium channel modulators and inhibitors of multi-drug resistance protein 5.
In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an antidepressant agent in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising an antianxiety agent in a pharmaceutically acceptable carrier.
In still yet an additional embodiment, the present invention also is ¨directed-to-a-kit-comprisingin-separate containers-in -a-single-package, pharmaceutical compositions for use in combination to treat an NKI receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier.
In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat depression and/or anxiety, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising an SSRI in a pharmaceutically acceptable carrier.
In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof, in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising a serotonin 5-HT3 receptor antagonist in a pharmaceutically acceptable carrier, and/or wherein a separate container comprises a pharmaceutical composition comprising a glucocorticoid in a pharmaceutically acceptable carrier.
In still yet an additional embodiment, the present invention also is directed to a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat emesis and/or nausea, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I or a - - --pharmaceutically -acceptable-salt-and/or- solvate-thereof,-in-a_pharmaceutically acceptable carrier, and wherein a separate container comprises ondansetron, and/or wherein a separate container comprises dexamethasone.
Another aspect of the invention is to provide a kit comprising, in separate containers in a single package, pharmaceutical compositions for use in combination to treat an NKi receptor mediated disease, wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of Formula I in a pharmaceutically acceptable carrier, and wherein, a separate container comprises a pharmaceutical composition comprising a therapeutic agent in a pharmaceutically acceptable carrier, the therapeutic agent being selected from the group consisting of: other types of NICI receptor antagonists, SSR1s, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2e receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multi-drug resistance protein 5.
Except where stated otherwise, the following definitions apply throughout the specification and claims. When any variable occurs more than one time in any moiety, its definition on each occurrence is independent of its definition at every other occurrence. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "alkoxy," etc.
Ac means acetyl.
AcOH (or HOAc) means acetic acid.
Boc means t-butoxycarbonyl.
Bu means butyl.
t-Bu or But means tertiary-butyl.
Bn means benzyl.
Cbz means carbobenzoxy (i.e., Ph-CH2-O-C(0)-).
DCM means dichloromethane.
DIEA means diisopropylethyl amine.
DMF means dimethylformamide.
DMAP means dimethylaminopyridine.
DMPU means N,N H -dimethyl propylene urea.
DMS0 means dimethylsulfoxide.
DPPA means diphenylphosphorazide.
Et means ethyl.
EDC means 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide hydrochloride.
FAB means fast atom bombardment.
HOTs means p-toluene sulfonic acid.
HATU means 0-(7-azabenzotriazol-1-y1)-N,N,N',N'-tetramethyluroniumhexafluorophosphate.
HPLC means High Performance Liquid Chromatography.
HRMS means high resolution mass spectroscopy.
LCMS means liquid chromatography/mass spectroscopy LiHMDS means lithium hexamethyldisilazide.
Me means methyl.
Me0H means methanol.
MS means mass spectroscopy.
Ms or mesyl means methane sulfonyl.
Ni (Ra) means Raney Ni.
OD means optical density.
Ph means phenyl i-PA (or IPA or iPA) means iso-propyl.
PPTS means pyridinium p-toluenesulfonic acid.
PTSA means p-toluene sulfonic acid.
PYBOP means (benzotriazol-1-yloxy)tripyrrolidino phosphonium hexafluorophosphate.
RT or rt means room temperature.
TBAF means tetrabutylammonium fluoride.
TBAI means tetrabutylammonium iodide.
TEA means trifluoroacetic acid.
THF means tetrahydrofuran.
TLC means Thin Layer Chromatography.
TMS means trimethylsilyl.
IMS_Cl_rneans_trimethylsilyl_chloride.
"Tosyl" means toluene sulfonyl.
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals.
Portions of chemical formulae enclosed in parentheses and/or brackets denote pendant groups. For example, -C(0)- refers to a carbonyl group (i.e., -C-), -N(alkyl)- refers to a divalent amine group with a pendant alkyl group ,OcH3 alkyl t\i (i.e., ¨IN¨) and -C(=NOCH3)-CH3 refers to --c-cH3 =
"Alkyl" means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain.
Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain.
More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain that may be straight or branched. The term "substituted alkyl" means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy and -C(0)0-alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
"Alkylene" means a divalent aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkylene groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Non-limiting examples of an alkylene group include methylene (i.e., -CH2-) and ethylidene (-CH2CH2- or -CH(CH3)-).
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term "alkenyl"
includes substituted alkenyl which means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and ¨S(alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl (i.e., vinyl), propenyl, n-butenyl, methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain that may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising_ab_o_ut_5_to_about_14sing_atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl"
can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-=lung examples ot suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, tetrazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. A
non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like, as well as partially saturated species such as, for example, indanyl, tetrahydronaphthyl and the like.
"Cycloalkylene" means a divalent cycloalkyl ring system, comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkylene rings contain about 5 to about 7 ring atoms.
The cycloalkylene can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
Non-limiting example of suitable monocyclic cycloalkylenes includes cyclopropylene (i.e., LI or ).
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred halogens are fluorine, chlorine and bromine. "Halogen" or "halo" substituted groups (e.g., haloalkyl groups) refers to groups substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms.
"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system, which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), Y1Y2N-alkyl-, Y1Y2NC(0)-, Y1Y2NS02- and -SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which __ form-moieties such-asrfor-example: ___ r--0 0 ro 410 0)3. and t.
"Heterocycloalkyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any ¨NH in a heterocycloalkyl ring may be present in protected form such as, for example, an -N(Boc), -N(CBz), -N(Tos) group and the like; such protected functional groups are also considered part of this invention. The heterocycloalkyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocycloalkyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, 0 or S, as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:

N
there is no -OH attached directly to carbons marked 2 and 5.
It should also be noted that tautomeric forms such as, for example, the moieties:
and N OH
are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. The "alkyl" portion of the hydroxyalkyl is preferably a lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" means an H-C(0)-, alkyl-C(0)- or cycloalkyl-C(0)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
"Aroyl" means an aryl-C(0)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-0- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Aryloxy" means an aryl-0- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as _previo_usly_de=ibed._N_onr_limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.
"Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthyltnio. The bond to the parent moiety is through the sulfur.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
"Alkoxycarbonyl" means an alkyl-O-00- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aryloxycarbonyl" means an aryl-O-C(0)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aralkoxycarbonyl" means an aralkyl-O-C(0)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(02)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(02)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "isolated" or "in isolated form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. The term "purified" or "in purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have one or more hydrogen atoms to satisfy the valences.
When a ring system (e.g., cycloalkyl, heterocycloaikyl, aryl, or heteroaryl) is substituted with a number of substituents varying within an expressly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under the existing conditions.
Thus, for example, a phenyl ring substituted with "n" substituents (where "n"
ranges from 0 to 5) can have 0 to 5 substituents, whereas it is understood that a pyridinyl ring substituted with "n" substituents has a number of substituents ranging from 0 to 4.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W.
Greene eta!, Protective Groups in Organic Synthesis (1991), Wiley, New York.
When any variable (e.g., aryl, heterocycloalkyl, R2, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein,, the term "comp.osition" is intended to ,encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
"Alkylheteroaryl" means an alkyl group attached to a parent moiety via a heteroaryl group.
"Alkylsulfinyl" means an alkyl-S(0)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.
"Aralkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through the alkenyl.
"Aralkyltio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
"Aryloxycarbonyl" means an aryl-O-C(0)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Arylsulfinyl" means an aryl-S(0)- group. Non-limiting examples of suitable arylsulfinyl groups include phenylsulfinyl and naphthylsulfinyl. The bond to the parent moiety is through the sulfinyl.
A carbamate group means a -0-C(0)-N(alkyl or aryl)- group, and a urea group means a -N(alkyl or aryl)-C(0)-N(alkyl or aryl)- group.
Representative carbamate and urea groups may include the following:
H3c2O-T-NA H3C>rNyN,,,is, H3C
H3c H30 "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising-about-3-to-about-10-carbon atoms, preferably about 5 to about 10 carbon atoms, which contains at least one carbon-carbon double bond.
Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
Non-limiting examples of suitable nnonocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkylamino" means a cycloalkyl group as defined herein attached to the parent moiety through a nitrogen atom.
"Cycloalkylaminocarbonyl" means a cyclic alkyl group attached to a nitrogen atom, which is attached to a carbonyl group; the whole may be referred to as a substituted amide.
"Heteroalkyl" means an alkyl as defined herein, in which at least one the atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
"Heteroaralkenyl" means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through the alkenyl.
"Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
"Heteroaralkylthio" means a heteroaryl-alkyl-S group wherein the group is attached to the parent moiety through the sulfur.
"Heteroarylsulfinyl" means a heteroaryl-S(0)- group wherein the heteroaryl is as defined herein and the heteroarylsulfinyl group is attached to the parent moiety through the sulfinyl.
"Heteroarylsulfonyl" means a heteroaryl-S(02) - group wherein the heteroaryl is as defined herein and the heteroarylsulfonyl group is attached to the-parent-moiety-through the sulfonyl.
"Heteroarylthio" means a heteroaryl-S- group wherein the heteroaryl is as defined herein and the heteroarylsulfinyl group is attached to the parent moiety through the sulfur.
"Heterocycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocycloalkenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocycloalkenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocycloalkenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocycloalkenyl groups include 1,2,3,4- tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limiting examples of suitable oxaheterocycloalkenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocycloalkenyl group is 7-oxabicyclo[2.2.1}heptenyl. Non-limiting examples of suitable monocyclic thiaheterocycloalkenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.
"Heterocyclic" means, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic organic groups having at least one 0, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered and may or may not have double bonds that lack delocalized pi electrons, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, e.g., 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- Or 3-morpholinyl, or 2- or 3-_th_im_orp h "Sulfonamide" means a sulfonyl group attached to a parent moiety through an amide.
As is well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom. For example:
¨N-CH3 represents 0 It should also be noted that throughout the specification and Claims appended hereto, that any formula, compound, moiety or chemical illustration with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences unless the context indicates a bond.
With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more"
and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art.
The wavy line ,n.n-rtP as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry.
For example, means containing both and When the stereochemistry in a structure is not expressly indicated, the structure can have a mixture of, or any of the individual possible stereoisomers. Thus, when the stereochemistry is not explicitly indicated in a structure, the structure includes all stereochernical configurations having the indicated connectivity (e.g., all possible enantiomers or diastereomers), as well as mixtures of such stereoisorners (e.g., racemic mixtures). For example, 111,--,1 N I
,--N

HN
. 0 110= L,r3 CH3 ' 'Means N N-Th N I N , I
.

OH ,....-N
: OH

HN

-,, CF3 tdri Wir CF3 CH3 1111, CH3 N N
/--7---i-N I N
OH ,..--N
OH
CF3. CF3 HN,co.,, HN,µ,00 el 0 el CF3 . CF3 N I N I
_.,-N ' 4,- OH
CF3 .- OH CF3 HN
I. HN
CF3 tda '23 Sill CF3 CH 3 111, ....
.eH3 N-_, N

,--N OH CF3 OH

0 =
140:1 ,,, HN,c ,s' 0 411:1 CF3 .....,3 ,H3 eH3 5 , and/or 11110 .
Lines drawn into the ring systems, such as, for example:
/\
indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug", as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
"Solvate" means .a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is H20.
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in antagonizing the neurokinin-1 receptor and thus producing the desired therapeutic effect in a suitable patient.
The compounds of Formula lform salts that are also within the scope of this invention. Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, dig luconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabarnines (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl -.43-and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others. Acids (and bases) which are generally considered suitable for the formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S.
Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, international J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Intl. Union of Pure and Applied Chemistry, pp. 330-331.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of Formula I and salts, solvates and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
Polymorphic forms of the compounds of Formula I, and of the salts, solvates, and/or prodrugs thereof, are intended to be included in the present invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and .prodrugs_of_the_compounds_as_well as_the_salts and solvates_ofthe prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention.
Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate"
"prodrug" and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds. "At least one", examples include 1-3, 1-2 or 1.
Compounds of Formula I are effective antagonists of the Nki receptor, and have an effect on its endogenous agonist, Substance P, at the NKi receptor site, and therefore, can be useful in treating diseases, disorders, or conditions caused or aggravated by the activity of the receptor.
The in vitro and in vivo NKi, NK2 and NK3 activities of the compounds of Formula I can be determined by various procedures known in the art, such as a test for their ability to inhibit the activity of the Nki agonist Substance P.
The percent inhibition of neurokinin agonist activity is the difference between the percent of maximum specific binding ("MSB") and 100%. The percent of MSB is defined by the following equation, wherein "dpm" represents "disintegrations per minute":
(dpm of unknown) - (dpm of nonspecific binding) % MSB = ____________________________________________________ X 100 (dpm of total binding) - (dpm of nonspecific binding) The concentration at which the compound produces 50% inhibition of binding is then used to determine an inhibition constant ("Ki") using the Chang-Prusoff equation.
In vivo activity may be measured by inhibition of an agonist-induced foot tapping in a gerbil, as described in Science, 281, 1640-1695 (1998), which is herein incorporated by reference in its entirety. It will be recognized that compounds of Formula I can exhibit Nki antagonist activities of varying 25- degrees. For instan-ce-rce-rtain-comp-ounds can-exhibit stronger Nki antagonist activities than others.
The compounds of the present invention exhibit potent affinities for the Nki receptor as measured by KJ values (in nM). The activities (potencies) for the compounds of the invention are determined by measuring their ki values.
The smaller the Ki value, the more active is a compound for antagonizing the Nki receptor. Compounds of the invention exhibit a wide range of activities.
The Nki average K1 values for compounds of Formula I generally range from 0.01 nM to about 1000 nM, preferably, from about 0.1 nM to about 100 nM, with values of from about 0.1 nM to about 10 nM being more preferred. Even more preferred are compounds having average K1 values of from 0.1 nM to about 5 nM for the NIci receptor. Especially preferred compounds have Nki average K1 values of from 0.1 nM to about 1 nM. Even more especially preferred compounds have NKi average K1 values of from 0.1 nM to about 0.3 nM. Compounds 2, 9, 10, 12, 14, 16, 19, 20, 23, 29, 30, 42, and 54 (see Table I above) have K1 values, respectively, of 0.12, 0.18, 0.1, 0.05, 0.1, 0.13, 0.1, 0.11, 0.12 0.11, 0.54, 0.28, and 0.12 nM.
Compounds of the Formula I have a number of utilities. For instance, the inventive compounds can be useful as antagonists of neurokinin receptors, particularly, NKi receptors in a mammal, such as a human. As such, they may be useful in treating and preventing one or more of a variety of mammalian (human and animal) disease states (physiological disorders, symptoms and diseases) in a patient in need of such treatment, wherein the disease states are selected from the group consisting of: (1) respiratory diseases (e.g., chronic lung disease, bronchitis, pneumonia, asthma, allergy, cough and bronchospasm), (2) inflammatory diseases (e.g., arthritis and psoriasis), (3) skin disorders (e.g., atopic dermatitis and contact dermatitis), (4) ophthalmologic disorders (e.g., retinitis, ocular hypertension and cataracts), (5) central nervous system conditions, such as depressions (e.g., neurotic depression), anxieties (e.g., general anxiety, social anxiety and panic anxiety disorders), phobias (e.g., social phobia), and bipolar disorder, (6) addictions (e.g., alcohol dependence and psychoactive substance abuse), (7) epilepsy, (8) nociception, (9) psychosis, (10) schizophrenia, (11) ¨.¨Alzheimerfs4isease,(12) AlDs related_dementia,__(_13)__T_ownes disease,_ (14) stress related disorders (e.g., post traumatic stress disorder), (15) obsessive/compulsive disorders, (16) eating disorders (e.g., bulimia, anorexia nervosa and binge eating), (17) sleep disorders, (18) mania, (19) premenstrual syndrome, (20) gastrointestinal disorders (e.g., irritable bowel syndrome, Crohn's disease, colitis, and emesis), (21) atherosclerosis, (22) fibrosing disorders (e.g., pulmonary fibrosis), (23) obesity, (24) Type II
diabetes, (25) pain related disorders (e.g., headaches, such as migraines, neuropathic pain, post-operative pain, and chronic pain syndromes), (26) bladder and genitourinary disorders (e.g., interstitial cystitis and urinary incontinence), (27) emesis (e.g., chemotherapy-induced (e.g., induced by cisplatin, doxorubicin, and taxane), radiation-induced, motion sickness, ethanol-induced, and post operative nausea and vomiting), and (28) nausea.
Preferably, the inventive compounds can be useful in treating and preventing one of the following mammalian (e.g., human) disease states in a patient in need of such treatment: respiratory diseases (e.g., cough), depression, anxiety, phobia, and bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorders, obsessive/compulsive disorder, bulimia, anorexia nervosa and binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, obesity, pain related disorders, bladder disorders, genitourinary disorders, emesis and nausea. In particular, the compounds according to Formula I are useful for treating disease states related to microvascular leakage and mucus secretion. Consequently, the compounds of the invention are especially useful in the treatment and prevention of asthma, emesis, nausea, depressions, anxieties, cough and pain related disorders, more especially, emesis, depression, anxiety and cough.
In another aspect, the invention relates to pharmaceutical compositions comprising at least one compound (e.g., one to three compounds, preferably, one compound) represented by Formula I and at least one pharmaceutically acceptable excipient or carrier. The invention also relates to the use of such pharmaceutical compositions in the treatment of mammalian (e.g., human) disease states, such as those listed above.
In still another aspect of the invention, a method is provided for _antagonizing_the_effecis_of_a_S_ubstance_P_at a_neurokinin-1 receptor site or for the blockade of one or more neurokinin-1 receptors in a mammal (i.e., a patient, e.g., a human) in need of such treatment, comprising administering to the mammal an effective amount of at least one (e.g., one) compound according to Formula I.
In another aspect of the invention, an effective amount of one or more of the inventive Nki receptor antagonists may be combined with an effective amount of one or more anti-depressant agents and/or one or more anti-anxiety agents (e.g., gepirone, gepirone hydrochloride, nefazodone, and netazodone hydrochloride (e.g., Serzone )) to treat depression and/or anxiety. U.S. 6,117,855 (2000) discloses a method for treating or preventing depression or anxiety with a combination therapy of a specific NK, receptor antagonist together with an anti-depressant and/or anti-anxiety agent. Thus, anti-depressant and/or anti-anxiety agents, such as those disclosed in U.S.
6,117,855 (2000), can be combined with one or more (e.g., one) compounds of the Formula I to treat depression and/or anxiety disease states in a mammal, preferably, a human.
In still another aspect of the invention, an effective amount of one or more (e.g., one) of the inventive NK, receptor antagonists may be combined with an effective amount of one or more (e.g., one) selective serotonin reuptake inhibitors ("SSRIs") to treat a variety of mammalian disease states, such as those described above. SSRIs alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. U.S. 6,162,805 (2000) discloses a method for treating obesity with a combination therapy of a NK, receptor antagonist and an SSRI.
One or more inventive compound(s) of the Formula I can be combined together with an SSRI(s) in a single pharmaceutical composition, or it can be administered simultaneously, concurrently or sequentially with an SSRI. This combination may be useful in the treatment and prevention of obesity or another of the above-identified human and animal disease states. In particular, an effective amount of at least one (e.g., one) compound having the Formula I, alone or together with an effective amount of at least one (e.g., one) selective serotonin reuptake inhibitor, can be useful in the treatment and prevention of depression, and/or anxiety.
Numerous chemical substances are known to alter the synaptic availability of serotonin through their inhibition of presynaptic reaccumulation of neuronally released serotonin. Representative SSRIs include, without limitation, the following: fluoxetine, fluoxetine hydrochloride (e.g., Prozac8), fluvoxamine, fluvoxamine maleate (e.g. Luvoe), paroxetine, paroxetine hydrochloride (e.g., Paxin, sertraline, sertraline hydrochloride (e.g., Zoloft ), citalopram, citalopram hydrobromide (e.g., Celexaml), duloxetine, duloxetine hydrochloride, venlafaxine, and venlafaxine hydrochloride (e.g., Effexoe).
Further SSRIs include those disclosed in U.S. 6,162,805 (2000). Other compounds can readily be evaluated to determine their ability to selectively inhibit serotonin reuptake. Thus, one aspect of the invention relates to a pharmaceutical composition comprising at least one (e.g., one) NKI receptor antagonist having the Formula I, at least one (e.g., one) SSRI, and at least one pharmaceutically acceptable excipient or carrier. Another aspect of the invention relates to a method of treating the above identified mammalian (e.g., human) disease states, the method comprising administering to a patient in need of such treatment an effective amount of a pharmaceutical composition comprising at least one (e.g., one) Nki receptor antagonist having the Formula I in combination with at least one (e.g., one) SSRI, such as one of those recited above, and at least one pharmaceutically acceptable excipient or carrier.
In a preferred aspect, the invention relates to a method of treating depression and anxiety, the method comprising administering to a patient in need of such treatment an effective amount of at least one (e.g., one) NIKi receptor antagonist having the Formula I in combination with at least one (e.g., one) SSRI, such as one of those described above. When an inventive NKi receptor antagonist is combined with an SSRI for administration to a patient in need of such treatment, the two active ingredients can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the two active ingredients are administered consecutively or sequentially, the inventive NKi receptor antagonist ipreferablydminis_tered before_the_administration of the SSRI.
It is another embodiment of the invention to treat a patient suffering from multiple ailments with a combination therapy, the therapy comprising administering to a patient (e.g., a mammal, preferably a human) in need of such treatment at least one compound of Formula I, and at least one other active ingredient (i.e., drug) used for treating one or more of the ailments being suffered by the patient. The compounds of Formula I and the other active ingredients can be administered sequentially, concurrently and/or simultaneously. The compounds of Formula I and the other active ingredients can be administered separately in any suitable dosage form. Preferably, administration is accomplished using an oral dosage forms or using a transdermal patches. The compounds of Formula I and the other active ingredients can be formulated together and administered in one combined dosage form.
Thus, the compounds of the invention may be employed alone or in combination with other active agents. Combination therapy includes the administration of two or more active ingredients to a patient in need of treatment. In addition to the above described NKi receptor antagonist/SSR1 combination therapy, the compounds having the Formula I may be combined with one or more other active agents, such as the following: other types of NKi receptor antagonists (e.g., those that are disclosed in neurokinin receptor antagonist patents cited above), prostanoids, H1 receptor antagonists, a-adrenergic receptor agonists, dopamine receptor agonists, melanocortin receptor agonists, endothelin receptor antagonists, endothelin converting enzyme inhibitors, angiotensin ((receptor antagonists, angiotensin converting enzyme inhibitors, neutral metalloendopeptidase inhibitors, ETA antagonists, renin inhibitors, serotonin 5-HT3 receptor antagonists (e.g., ondansetron, ondansetron hydrochloride (e.g., Zolfrae), palonosetron, granisetron, and granisetron hydrochloride (e.g., Kytri18), serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids (e.g., dexamethasone), rho kinase inhibitors, potassium channel modulators and/or inhibitors of multi-drug resistance protein 5.
Particularly useful therapeutic agents for combination therapy with compounds of the invention are the following: prostanoids, such as prostaglandin-El; -a-adrenergic-agonists-,-such as phentolamine mesylate;
dopamine receptor agonists, such as apomorphine; angiotensin II
antagonists, such as losartan, irbesartan, valsartan and candesartan; ETA
antagonists, such as bosentan and ABT-627; serotonin 5-HT3 receptor antagonists, such as ondansetron; and glucocorticoids, such as dexamethasone. In preferred embodiments of the invention, the inventive compounds can be combined with: other types of NIki receptor antagonists, SSR1s, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids and/or inhibitors of multi-drug resistance protein 5.
Another embodiment of this invention is directed to a method for treating a physiological disorder, symptom or disease in a patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of Formula I, and an effective amount of at least one active ingredient selected from the group consisting of: other NIKi receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor agonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2c receptor agonists, nociceptin receptor agonists, glucocorticoids and inhibitors of multidrug resistance protein 5, wherein the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorder, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, cough, emesis and nausea.
Pharmaceutical compositions may contain from about 0.1 to about 99.9 weight percent, or from about 5 to about 95 weight percent, or from about 20 to about 80 weight percent of active ingredient (compound of the Formula l).
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally.
The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units, in any of the forms described herein, comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid "more than one pharmaceutically active agents". The term "bulk composition" means material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the aforesaid bulk composition and individual dosage units.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 4000 mg, preferably from about 0.02 mg to about 1000 mg, more preferably from about 0.3 mg to about 500 mg, and most preferably from about 0.04 mg to about 250 mg according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.
Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.02 mg/day to about 2000 mg/day, in two to four divided doses.
The pharmaceutical compositions of the invention may be administered from about 1 to about 5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
The quantity of NKi receptor antagonist in combination with a selective serotonin reuptake inhibitor ("SSRI") in a unit dose of preparation may be from about 10 to about 300 mg of NKi receptor antagonist combined with from about40-to-about-1-00-mg-of-SSRI¨In-another combination the_quantity of NIKi receptor antagonist in combination with a SSRI in a unit dose of preparation may be from about 50 to about 300 mg of NIKi receptor antagonist combined with from about 10 to about 100 mg of SSRI. In another combination the quantity of NKi receptor antagonist in combination with SSRI
in a unit dose of preparation may be from about 50 to about 300 mg of MCI
receptor antagonist combined with from about 20 to about 50 mg of SSRI.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated.

Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required. Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of the invention may be administered, if necessary.
Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
Specific dosage and treatment regimens for any particular patient may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex and diet of the patient, the time of administration, the rate of excretion, the specific drug combination, the severity and course of the symptoms being treated, the patient's disposition to the condition being treated and the judgment of the treating physician. Determination of the proper dosage regimen for a particular situation is within the skill of the art.
EXAMPLES
The invention disclosed herein is exemplified by the following preparations and examples.
PREPARATIVE-EXAMPLE -1_ IN,As! CF, HN
CF, =

Step 1:

CI
I-1,N ,,CN CF, 0 N= CN CF, C bzN 4101 eF3 Et3N. CH2C12 CbzN
CF, 42h 10 la In a 25 mL round-bottomed flask, Compound 42b (0.253 g, 0.42 mmol, 1.0 equiv) was taken up in 5 mL of CH2Cl2, and the resulting reaction mixture was cooled to 0 C in an ice bath. Et3N (0.088 mL, 0.63 mmol, 1.5 equiv) followed by 4-chlorobutyryl chloride (0.065 mL, 0.5 mmol, 1.2 equiv) was then added to the reaction mixture, which was subsequently slowly warmed to room temperature and was stirred for 14 hrs. The progress of the reaction was monitored by TLC (60:40 Et0Ac/hexane) and MS. Upon completion, the reaction mixture was diluted with CH2Cl2, quenched with saturated aqueous NaHCO3, followed by brine. The organic layer was dried over Na2SO4 and concentrated to give crude Compound la (0.3 g), which was used in the next step without further purification.
Electrospray MS [M+1] 724.4.
Step 2:
(--Ne CN CF, N SCN CF, 60% NaH, 0 THF Chats! 110 CbzN CF, CF, la 113 In a flame-dried 25 mL round-bottomed flask, Compound la (0.3 g, 0.4 mmol, 1.0 equiv) was taken up in, dry THF. To this reaction mixture, 60%
NaH (0.025 g, 0.62 mmol, 1.5 equiv) was added, and reaction mixture was stirred at room temperature-fdr-2-liFs7Th¨e-pTC4reSs¨dfilie redotioTi`was monitored by TLC (60:40 Et0Ac/hexane) and MS. Upon completion, the reaction mixture was diluted with Et0Ac and quenched with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give Compound lb (0.25 g), which was used in the next step without further purification.
Step 3:

r-Nfo ryo c, .,CN CF,,CN CF, 20% PdOti, 1NPMe0H, H3(9) CbzN 41111 CF, HN CF, Compound lb (0.25 g, 0.37 mmol, 1.0 equiv) was dissolved in dry Me0H (2.0 mL) and was treated with 20% Pd(OH)2 (60% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and was monitored by TLC (60:40 Et0Acihexane). The reaction was completed in 45 min, and the reaction mixture was then filtered through CELITETm (diatomaceous earth), washed with Et0Ac, and concentrated to give a crude product. Purification was carried out using preparative plate chromatography (60/40 Et0Adhexane) to give Compound 1 (0.10 g, 49%).
Electrospray MS [M+1] 554.3.
HRMS (FAB) calculated for C28H29F6N302(M+1) 554.2242, found 554.2249.

CF, HN
CF, Example 2 Step 1:
H
H2N .,,CN CF, ..,CN CF, CbzN 40 E, ,C4 l,N CH CbzN ISO
CF, CF, 42b 2a In a 25 ml round-bottomed flask, Compound 42h (0.3264 g, 0.44 mmol, 1.0 equiv) was taken up in 5 mL of THF, and the reaction mixture was cooled to 0 C in an ice bath. Et3N (0.073 mL, 0.44 mmol, 1.2 equiv) followed by 2-chioroetnyi cniorotormate (0.054 mL, 0.44 mmol, 1.2 equiv) was then added to the reaction mixture, which was slowly warmed to room temperature and stirred for 14 hrs. The progress of the reaction was monitored by TLC
(40:60 Et0Ac/hexane) and MS. The reaction did not go to completion, and hence was diluted with Et0Ac and quenched with saturated NaHCO3 followed by brine. The organic layer was dried over Na2SO4 and concentrated to give (0.3 g) crude product, which was subjected to BIOTAGE chromatography (40:60 Et0Adhexane) to give Compound 2a (0.125 g).
Electrospray MS [M-I-1] 712.4.
Step 2:
CI
ti oN CF, CN
T CF, 6D%NaH, CF, THF
CbzN 410 CbzN
C
2a 2b In a flame-dried 25 ml round-bottomed flask, Compound 2a (0.125 g, 0.175 mmol, 1.0 equiv) was taken up in dry THF. To this reaction mixture, 60% NaH (0.10 g, 0.26 mmol, 1.5 equiv) was added and reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (40:60 Et0Ac/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with Et0Ac and quenched with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give Compound 2b(0.11 g), which was used in the next step without further purification.
Electrospray MS [M+1] 676.2.
Step 3:
,,CN CF, 20% POOH, CN CF, Me0H, Ng) CbzN HN o410 CF, CF, 2b Compound 2 Compound 2b (0.11 g, 0.16 mmol, 1.0 equiv) was dissolved in dry Me0H (2.0 mL) and was treated with 20% Pd(OH)2 (60% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 Et0Ac/hexane). The reaction was completed in 45 min, filtered through CELITE, washed with Et0Ac, and concentrated to give a crude product. The crude product was purified using preparative plate chromatography (45/55 Et0Ac/ hexane) to give Compound 2 (0.04 g, 45%).
Electrospray MS [M+1} 542.3.
HRMS (FAB) calculated for C26H26F6I\1303(M+1) 542.1897, found 542.1878.
PREPARATIVE Example 3 and Example 4 ,o T OH 14),L.e,0 pH
CF, CF, CF, OF, Example 3 Example 4 Hz_10 H
N, OH N1.-e T PH
Nc 0 -N CF3 OF3 "k--N CF, NaBH4, EtOH
HN , 0 410 HN 0 40 1-IN 0 CF, CF, CF, NaBH4 (60 mg, 1.53 mmol, 8 equiv.) was added in portions to a solution of Compound 30 (109 mg, ¨0.19 mmol, 1 equiv.) in absolute ethanol (2 mL) at 0 C. After stirring at 0 C for 30 minutes, TLC (Me0H/CH2C12 =10%) analysis of the reaction mixture showed only product. The product was purified by BIOTAGE chromatography (2-10% Me0H in CH2Cl2), to provide a pure mixture of two diastereomers. The two diastereomers were separated using Chiral HPLC (ChialCel OD, IPA/Hexane=10%) to give Example 3, MS
[M+1]+ 573.1; and Example 4, MS [M+1] 573.1.

N, N
CF, HN
CF, Compound 5 Step A:
NHBoc NHBoc HO CF, a MsCI, NEµ NC CF, b. KCN, DMF
CbzN CbzN 410 CF, CF, Compound 26a Compound 5b MsCI (0.102 mL, 1.32 mmol) was added to a solution of Compound 26a (0.375 g, 0.528 mmol) and Et3N (0.368 mL, 2.64 mmol) in CH2Cl2 (5.0 mL) at 0 C. The reaction mixture was quenched with water (15.0 mL) after 30 minutes and then diluted with CH2Cl2 (50 mL). The resulting aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude mesylate was taken up in DMF (3.0 mL) and treated with KCN (0.344 g, 5.28 mmol). The resulting mixture was heated at 100 C for 12 hours before it was cooled to room temperature. The reaction mixture was diluted with Et0Ac (100 mL) and washed with water (3 x 15 mL).
The organic layer was then washed with brine (25 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified by BIOTAGE chromatography (hexane/Et0Ac, v/v = 7/1) to give Compound 5b (0.14 g, 37% for 2 steps).
Step B:
N.
NHBoc NC CF, a. TFA NC CF, CbzN b. HC(0)NHNHC(0)H, TMSCI, Bt,N, Py CF, CbzN
CF
lit 3 Compound 5b Compound 5c A solution of Compound 5b (0.14 g, 0.195 mmol) in TFA (2.5 mL) was stirred at room temperature for 20 minutes before the solvent was removed under reduced pressure. The residue was taken up in Et0Ac (50 mL) and washed with a NaOH solution (4.0 N, 15 mL). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and then dried over MgSO4. After filtration and concentration, the crude product was passed through a short pad of silica gel with Et0Ac/Me0H (v/v = 10/1) as eluent, to provide an amine (90 mg) after solvent removal. The amine was taken up in pyridine (1.0 mL) and treated with HC(0)NHNHC(0)H (38.3 mg, 0.435 mmol), TMSCI (0.276 mL, 2.175 mmol) and Et3N (0.152 mL, 1.088 mmol) at room temperature in a sealed tube. The reaction mixture was then heated at 100 C for 2.5 hours before it was cooled down to room temperature. The mixture was then diluted with Et0Ac (40 mL) and washed with HCI (10 mL, 2.0 N). The resulting aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (25 mL), and dried over MgSO4.
After filtration and concentration, the crude product was purified using BIOTAGE chromatography (Et0Ac/Me0H, v/v = 10/1) to give Compound 5c (40 mg, 31% for 2 steps).
Step C:
N, NN, N, N-g N
NC CF, 49-j 1-12, Pd CF, NC CF,(OH)2/C, Et0H
NC"'"%, CbzN o40 3 .
CF, HN HN

Compound 5c Compound 5 Compound 5d Compound 5c (40 mg, 0.0595 mmol) in Et0H (2.0 mL) was treated at room temperature with Pd(OH)2/C (8 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure, and the crude product was purified using preparative TLC (Et0Ac/Me0H, v/v = 40/1) to give Compound 5 (18 mg, 56%, Electrospray MS [M+11 538.1.) and Compound 5d (6 mg, 19%, Electrospray MS [M+11 538.1.).

CH, CF, HN
CF, Compound 6 Step A:
02N, OH CF, ()Pk CH, CF, a. MaCt NEt, b. NaBH4, DMSO
CbzN
CbzN 40 CF, Compound 23d Compound 6a MsCI (75 mL, 0.969 mmol) was added to a solution of Compound 23d (0.248 g, 0.388 mmol) and Et3N (0.27 mL, 1.94 mmol) in CH2Cl2 (3.0 mL) at room temperature. The reaction was quenched with water (10.0 mL) after 30 minutes and diluted with CH2Cl2 (30 mL). The aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude mesylate was taken up in anhydrous DMSO (3.0 mL) and treated with NaBH4 (59.0 mg, 1.552 mmol). The reaction mixture was heated at 85 C for 48 hours before it was cooled down to room temperature.
The mixture was then diluted with Et0Ac (50 mL) and washed with aqueous HC1(10 mL, 1.0 M). The resulting aqueous phase was extracted with Et0Ac (3x 15 mL). The combined organic layers were washed with water (3 x 15 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using B1OTAGE chromatography (hexane/Et0Ac, v/v = 5/1) to give Compound Ga (0.11 g, 45% for 2 steps).
Step B:
=

03Nõ CH3 CF3 \1.-N, CH3 CF, a. Zn, HOAc CbaN o b. HC(0)NHNHC(0)H, TMSCI, Et3N, Py CbzN
CF, ________________________________________ CF, Compound 6a Compound 6b A mixture of Compound 6a (0.11 g, 0.176 mmol) and Zn dust (0.114 g, 1.76 mmol) in HOAc (1.5 mL) was heated at 60 C for 2 hours. The reaction mixture was cooled down and filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the residue was taken up in Et0Ac (25 mL) and washed with a NaOH solution (4.0 N, 10 mL). The resulting aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude amine (67.1 mg, 0.113 mmol) was taken up in pyridine (1.0 mL) and treated with HC(0)NHNHC(0)H (29.8 mg, 0.339 mmol), TMSCI (0.214 mL, 1.69 mmol) and Et3N (0.118 mL, 0.847 mmol) at room temperature in a sealed tube. The mixture was then heated at 100 C for 2.5 hours before it was cooled down to room temperature. The mixture was then diluted with Et0Ac (40 mL) and washed with HCI (10 mL, 2.0 N). The resulting aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO4.
After filtration and concentration, the crude product was purified using BIOTAGE chromatography (Et0Ac/Me0H, v/v = 20/1) to give Compound 6b (37 mg, 33% for 2 steps).
Step C:
,N
Ns,- -I

CF, \=-N, CH3 Pd(OH)21C, Et0H CF, CbzN
Cr, )5 CF3 =
Compound 6b Compound 6 t,ompouna o in.5 mg, 0.0565 mmol) in Et0H (2.0 mL) was treated at room temperature with Pd(OH)2/C (7.3 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the crude product was purified using preparative TLC (Et0Ac/Me0H/Et3N, v/v/v 40/1/0.1) to give Compound 6 (20 mg, 69%). Electrospray MS [M+1]+ 513.1.

NC CP, Compound 7 Step A:
N, NN
iN
Ho P¨j cF3 a. Dess-Martin Periodinane NC P--/ CP, b.HONH,.HCI, Na0Ac, Et0H
c. PhH
CbzN tet CbzN o40 CF3 ______________________________________________________ CP, Compound 12a Compound 7a Dess-Martin Periodinane (0.114 g, 0.268 mmol) was added to a mixture of Compound 12a (70.5 mg, 0.107 mmol) and NaHCO3 (0.112 g, 1.34 mmol) in CH2Cl2 (3.0 mL) at room temperature. The reaction was stirred for 1 hour before it was diluted with the addition of Et0Ac (30 mL) and water (10 mL). The organic phase was washed with saturated Na2S203 solution (3 x 10 mL). The combined aqueous phases were extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with a NaOH solution (10 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude aldehyde (70.5 mg, 0.107 mmol) was dissolved in Et0H (3.0 mL) and treated with HONH2-11C1 (74.4 mg, 1.07 mmol) and Na0Ac (43.9 mg, 0.535 mmol) at room temperature. The reaction mixture was stirred for 12 hours before it was diluted with Et0Ac (20 mL) and washed with aqueous NaHCO3 (10 mL). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude oxime was obtained (63 mg, 0.093 mmol) which was taken up in benzene (2.0 mL) and treated with 1,1'-oxalyldiimidazole (35.4 mg, 0.186 mmol). The reaction mixture was heated at 80 C for 3 hours before it was cooled down to room temperature and diluted with Et0Ac (20 mL) and washed with aqueous HCI (0.5 N, 5 mL). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE
chromatography (Et0Ac) to give Compound 7a (39 mg, 55% for 3 steps).
Step B:
N,N

NC ;14-1 CF, NC ¨
CF, H2, Pd(OH)/C, Et0H
CbzN a HN
CF, CF, Compound 7a Compound 7 Compound 7a (39 mg, 0.059 mmol) in Et0H (2.5 mL) was treated at room temperature with Pd(OH)2/C (7.8 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the crude product was purified using preparative TLC (Et0Ac/Et3N, v/v = 100/0.1) to give Compound 7 (12.2 mg, 40%). Electrospray MS [mi-1] 524.3.

o e;!`.1 CF, HN
CF, Compound 8 Step A:
c"N a. Dess-Martin Periodinane 0 N,N
N¨ll HO CF b. 2-methy1-2-butene, NaC102 NaH2PO4, tert-butanot HC0 CF, c. TMSCHN2, Me0H, PhH
CbaN , CbaN
CF, CF, Compound 12a Compound 8a Dess-Martin Periodinane (0.325 g, 0.767 mmol) was added to a mixture of Compound 12a (0.202 g, 0.306 mmol) and NaHCO3 (0.322 g, 3.83 mmol) in CH2Cl2 (5.0 mL) at room temperature. The reaction was stirred for 1 hour before it was diluted with Et0Ac (50 mL) and water (10 mL). The organic phase was washed with saturated Na2S203 solution (3 x 15 mL). The combined aqueous phases were extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude aldehyde (0.202 g) was taken up in tert-butanol (4.0 mL) and water (1.0 mL) and treated with NaH2PO4-1-120 (84.4 mg, 0.612 mmol), NaC102 (96.8 mg, 1.07 mmol) and 2-methyl-2-butene (0.227 mL, 2.14 mmol) successively. The reaction mixture was stirred for 2 hours and then diluted with Et0Ac (30 mL) and washed with aqueous NH4CI. The resulting aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4.
After filtration and concentration, the crude acid was dissolved in benzene (4.0 mL) and Me0H (1.0 mL). The resulting solution was treated with TMSCHN2 (0.306 mL, 0.612 mmol) at room temperature and stirred for 20 minutes. Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 5/1 to 1/3) to give Compound 8a (62 mg, 29% for 3 steps).

Step B:
N, N, H3C0 0 CF, H3, Pd(OH)2/C, EtOH H3co CF , CbzN 0001 CF, HN (-3 Compound 8a Compound 8 Compound 8a (62 mg, 0.090 mmol) in EtOH (3.0 mL) was treated at room temperature with Pd(OH)21C (12.4 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (Et0Ac/Me0H, v/v = 6/1) to give Compound 8 (42 mg, 84%). Electrospray MS [M+1]+ 557.3.

L-N.,CN CF, HN
CF, Step 1:
CI

H2N,,CN CF, cjit CN CF, =
CbzN 40 Toluene CbzN
CF3 RTemp - 80 C CF3 9a In a 25 ml round-bottomed flask, Compound 42h (0.21 g, 0.35 mmol, 1.0 equiv) was taken up in 2 mL of toluene. 3-chloropropionyl chloride (0.037 mL, 0.38 mmol, 1.1 equiv) was then added to the reaction mixture, which was stirred at room temperature for five hrs. The progress of the reaction was monitored by TLC (60:40 Et0Ac/hexane) and MS, which showed some starting material was still present. The reaction mixture was thus heated to 80 C. Upon completion of the reaction after a further hour of heating, the mixture was concentrated to give crude product Compound 9a (0.2 g), which was used in the next step without further purification.
Step 2:

CF, o 60% NaH in CbzN CH,C1,/DME
(4/1) CbzN

=

9a b In a flame-dried 25 ml round-bottomed flask, Compound 9a (0.2 g, 0.287 mmol, 1.0 equiv) was taken up in a 0.5 M solution of dry CH2Cl2/DMF
(4/1) ratio (4.59 mL/1.15 mL). To this mixture a 0.5 M solution of 60% NaH
(0.012 g, 0.316 mmol, 1.1 equiv) in dry CH2Cl2/DMF (4/1 ratio; 5.06 mL/1.26 mL) was very slowly added using a syringe pump over a period of 3.5 hrs and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (40:60 Et0Ac/hexane) and MS. The reaction went to 60% completion, and was then diluted with CH2Cl2 and quenched with saturated aqueous NH4CI. The organic layer was dried over Na2SO4 and concentrated to give crude product (0.18 g), which was purified using BIOTAGE chromatography (30/70 Et0Ac/ hexane) to give Compound 9b (0.125 g).
Electrospray MS [M+1] 660.2.
Step 3:
L .,,CN CF3 CN
20% Pd0H, CF3 Me0H, 112(g) CbzN RN 40 9b 9 Compound 9b (0.125 g, 0.189 mmol, 1.0 equiv) was dissolved in dry Me0H (1.0 mL) and was treated with 20% Pd(OH)2 (60% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (60:40 Et0Ac/hexane). The reaction was completed in 20 min, and the reaction mixture was filtered through CELITE, washed using Et0Ac, and concentrated to give crude product. Purification was carried out using prep plate chromatography (45/55 Et0Ac/ hexane) to give Compound 9 (0.071g, 71%).
Electrospray MS [M+1] 526.3.
HRMS (FAB) calculated for C26H26F6N302(M+1) 526.1932, found 526.1929.

0 cAiN
H2N CF, CF, Compound 10 Step A:
N, 0 N. ,,N
H3C0 CF, H,N CF, HN
NH,, Me0H
HN o 00 CF, _____________________________________________________ CF, Compound 8 Compound 10 A solution of Compound 8 (35 mg, 0.063 mmol) in ammonia methanol solution (3.0 mL, 7.0 M) in a Parr bomb was heated at 80 C for 5 days. The system was cooled to room temperature and solvent was removed under reduced pressure. The crude product was purified using BIOTAGE
chromatography (Et0Ac/Me0H, v/v = 10/1) to give Compound 10 (26.8 mg, 79%). Electrospray MS [M+1]+ 542.1.

OH
CF, HN OP

Example 11 Step 1:

o wrsLf OH
CF3 MeMgBr, THF OF, CbaN CbzN 40 CF CF, 30b 11a A solution of methylmagnesium bromide in tert-butylether (0.42 mL, 1.0M, 0.42 mmol, 6.2 equiv.) was syringed into a solution of Compound 30b (48 mg, 0.068 mmol, 1.0 equiv.) in anhydrous THF (1 mL) at 0 C. The reaction mixture was then warmed up to room temperature. After TLC (Et0Ac eluent) showed that the reaction was complete, the reaction mixture was diluted with ether and washed with saturated aqueous NH4CI solution. The combined organic layers were dried over MgSO4, filtered and concentrated to give crude product, Compound 11a, which was used in the next step without purification.
Step 2:

OH N,N-t N
CF, Pd( OHOHWC, H2 OF, CbzN HN 0 CF CF, (53% from 30b) 11a 11 Using the same procedure as that of Example 31, Step 6, the crude Compound 11a was hydrogenated to give pure Example 30b (yield 52.6%
from Compound 11). MS [M+1r 587.1.

N, IN
HO ,N¨j CFs HN
CF, Compound 12 Step A:
N, HO PH2 CF s sr-.1 HO .z.N CFs CHONHNHCHO, TMSCI, Et3N, Py GbaN
CF, _____________________________________________ CbzN

Compound 23d Compound 12a HC(0)NHNHC(0)H (0.28 g, 3.18 mmol), TMSCI (2.0 mL, 15.9 mmol) and Et3N (1.1 mL, 7.95 mmol) were added successively to a solution of Compound 23d (0.647 g, 1.06 mmol) in pyridine (5.0 mL) at room temperature in a sealed tube. The mixture was then heated at 100 C for 2.5 hours before it was cooled down to room temperature. The mixture was then diluted with Et0Ac (100 mL) and washed with HCI (35 mL, 2.0 N). The aqueous phase was extracted with Et0Ac (3 x 25 mL), and the combined organic layers were washed with water (15 mL), brine (25 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (Et0Ac/Me0H, v/v = 5/1) to give Compound 12a (0.48 g, 68%).
Step b:
N.
j/N1N, HO P"--- CF, H2, Pd(OH)1C, Et0H HO= CF, Cb2N 40 HN
CF, CF3 Compound 12a Compound 12 Compound 12a (32.6 mg, 0.049 mmol) in Et0H (2.0 mL) was treated at room temperature with Pd(OH)21C (6.5 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was then filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (Et0Ac/Me0H eluent, v/v = 6/1) to give Compound 12 (17.2 mg, 66%). Electrospray MS [M-1-1]+ 529.1.
PREPARATIVE EXAMPLE 13 and 14 N, N
11_#
1-13C0"¨ , CF, 11300 CF, HNHN
CF, CF, Compound 13 Compound 14 Step A:
NN
H3C0 NH2 CF, H3C0 CF, HC(0)NHNHC(0)H, TMSCI, Et,N, Py CbzN 0 40 CbzN
CF, CF, Compound 26a Compound 14a HC(0)NHNHC(0)H (67.1 mg, 0.762 mmol), TMSCI (0.484 mL, 3.81 mmol) and Et3N (0.266 mL, 1.905 mmol) were added successively to a solution of Compound 26a (0.155 g, 0.254 mmol) in pyridine (2.0 mL) at room temperature in a sealed tube. The mixture was then heated at 100 C for 2.5 hours before it was cooled down to room temperature. The mixture was diluted with Et0Ac (40 mL) and washed with HCI (15 mL, 2.0 N). The aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (25 mL), and dried over MgSO4.
After filtration and concentration, the crude product was purified using BIOTAGE chromatography (Et0Ac/Me0H, v/v = 10/1) eluent to give Compound 14a (0.129 g, 75%).

Step N , c.'" c;.NN

.N
H2, Pd(OH)2/C, Et0H CF, H3C0 CF3 CbaN c,, HN 001 0 MN
CF CF= , Compound 14a Compound 13 Compound 14 Compound 14a (129 mg, 0.19 mmol) in Et0H (4.0 mL) was treated at room temperature with Pd(OH)2/C (25.8 mg, 10 wt%) and hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the crude product was purified using preparative TLC (Et0Ac/Et3N, v/v = 100/0.1) to give Compound 13 (36 mg, 35%, Electrospray MS [M+1] 543.1.) and Compound 14 (30 mg, 29%, Electrospray MS [M+1] 543.1.).

0,p ('NH
H CF, 3 H = 0 MN . 0 =
0F, Compound 16 Step A:
N,NH ('N,NH
N40 CF3N' a. Dess-Martin periodinane H3C0 * H '= 0 CF3 b.p-Me0BnNH2, NaBH(OAc), Dbz1,1 CICH,CH2CI CbzN

Compound 23g Compound 15a Dess-Martin Periodinane (57.7 mg, 0.136 mmol) was added to a mixture of Compound 23g (46 mg, 0.0678 mmol) and NaHCO3 (57 mg, 0.678 mmol) in CH2Cl2 (2.5 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with Et0Ac (20 mL) and water (10 mL).

The organic phase was washed with saturated Na2S203 solution (3x10 mL).
The combined aqueous phases were extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with NaOH solution (10 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude aldehyde (46 mg, 0.0679 mmol) was taken up in CICH2CH2CI (1.0 mL) and treated with 4A molecular sieves (15 mg) and para-methoxybenzyl amine (26.7111, 0.204 mmol), followed with addition of NaBH(OAc)3 (86.4 mg, 0.408 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. The system was then diluted with Et0Ac (20 mL) and washed with aqueous NaHCO3 (10 mL). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE
chromatography (hexane/Et0Ac, v/v = 2/3) to give Compound 15a (38 mg, 70% for 2 steps).
Step Bi N,N
(' NH
CF, H2N--" CF3 NH,,CO2H, Pd/C, MeCH

CtaN 40 HN

Compound 15a Compound 15b A mixture of Compound 15a (46.6 mg, 0.0584 mmol), Pd/C (46.6 mg, 10 wt%), and NH4CO2H (36.8 mg, 0.584 mmol) in Me0H (2.0 mL) was heated at reflux for 5 hours. The mixture was cooled to room temperature and filtered through a short pad of CELITE, and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure to give a crude product, which was taken up with Et0Ac (20 mL) and washed with aqueous NaHCO3 (10 mL). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using preparative TLC (Me0H/Et0Ac, v/v = 1/10) to give Compound 15b (18 mg, 57%).
Step C:
ej'NH 0õ0N'NH
CF, H3C 0 CF, MsCI, NEt3, CH2C12 CF, CF, Compound 15b Compound 15 MsCI (2.5 H.L, 0.0324 mmol) was added to a solution of Compound 15b (8.8 mg, 0.0162 mmol) and Et3N (5.4 L, 0.0388 mmol) in CH2Cl2 (1.0 mL) at 0 C. The reaction was quenched with water (5.0 mL) in 30 minutes and diluted with Et0Ac (15 mL). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 1/5) to give Compound 15 (7.2 mg, 72%). Electrospray MS [M+1J+ 622.3.

pi HN
CF, HN
CF, compound 16 Step 1:
H H
HN¨/
Ni NI
.--0O211 CF, CF3 HATU, EtNH, CbzN 40 CbzN 40 CF, DMF CF, 31h 16a Using the same procedure as that of Example 30, Step 1, Compound 16a was prepared using ethylamine in the place of N,N-dimethylamine hydrochloride salt, and without using diisopropyl ethyl amine. The crude product was used in the next step without purification.
Step 2:
H
NY RN¨'I fO HN--/

0 PCIPH)2/C, H2 CF
CF HN-" " CF3 (71% from CW8) 16a compound 16 Using the same procedure as that of Example 31, Step 6, the crude Compound 16a was hydrogenated to give pure Example 16 (yield 70.5%
from Compound 16). Ms Em-or 600.1.

HN
'CF3 Example 17 Step 1:
H H
,s¨CO2H CF3 NNCF3 DMAP, EDC
CbzN 40 CbzN 0 40 CF3 Et0H, CH3C12 CF, 31h S 17a A solution of Compound 31h (46.3 mg, 0.066 mmol, 1.0 equiv.) in anhydrous dichloromethane (1 mL) was cooled to 0 C. To this solution was added sequentially DMAP (8 mg, 0.066 mmol, 1.0 equiv.), and ethanol (36 ,L). The reaction mixture was allowed to warm up to room temperature, and then concentrated to dryness. The residue was taken up into Et0Ac and washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, Compound 17a, which was used in the next step without purification.
Step 2:
N'N11-se N
CF, 0 CF, Pd(OH)2/C, H2 =
CbzN
CF, HN
(46% from 31h) CF3 17a Using the same procedure as that of Example 31, Step 6, the crude Compound 17a was hydrogenated to give pure 17 (yield 46% from Compound 31h). MS [M+1] 601.1.

HO,N), CF, \s0 RN
CF, Compound 18 Step A:
'NH
CF, HO, j CF, NH,OH, Et0H 0 CF, RN

Compound 19 Compound 18 Compound 19 (10 mg, 0.0175 mmol) in Et0H (1.5 mL) was treated with HONH2-1-1C1 (12.2 mg, 0.175 mmol) and Na0Ac (7.2 mg, 0.0876 mmol) at room temperature. The reaction mixture was then stirred at 60 C for 12 hours. The mixture was diluted with Et0Ac (20 mL) and washed with aqueous NaHCO3. The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified by preparative TLC (hexane/Et0Ac, v/v = 2/3) to give Compound 18 (10 mg, 98%). Electrospray MS [M+1]* 586.1.

(-N-NH
N40 CF, CF, Compound 19 Step A:
14,NHN'NH
N40 CF, a. Dess-Martin periodinane ()=---Cõ CF, b. VinylMgBr, THF
CbzN
C. Dess-Martin periodinane CF, CbzN n Wi Compound 23h Compound 19a Dess-Martin Periodinane (0.252 g, 0.595 mmol) was added to a mixture of Compound 23h.(0.202 g, 0.297 mmol) and NaHCO3 (0.25 g, 2,97 mmol) in CH2Cl2 (4.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with Et0Ac (50 mL) and water (10 mL).

The organic phase was washed with a saturated Na2S203 solution (3x15 mL).
The combined aqueous phases were extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude aldehyde (0.202 g) was taken up in anhydrous THF
(4.0 mL) and was treated with CH3MgBr (1.19 mL, 1.19 mmol, 1.0 M in THF) at -78 C. The reaction temperature was slowly increased to room temperature and the reaction was quenched in 2 hours by the slow addition of saturated aqueous NH4CI solution (10 mL). The reaction mixture was then diluted with EtOAc (50 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly acidic. The aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude secondary alcohol (0.21 awes taken up in CH2Cl2 (5.0 mL) and treated with Dess-Martin Periodinane (0.379 g, 0.894 mmol) and NaHCO3 (0.375 g, 4.47 mmol) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with Et0Ac (50 mL) and water (10 mL). The organic phase was washed with saturated Na2S203 solution (3x15 mL). The combined aqueous phases were extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with aqueous NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude produce was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v 1/1) to give Compound 19a (90 mg, 43% for 3 steps).
Step B:
NH ,NH
O. CF3 0 H2, Pd(OH)2/C, Et0H 0),, NA u3 CbzN

1-",- 3 Compound 19a Compound 19 Compound 19a (57.4 mg, 0.0816 mmol) in Et0H (3.0 mL) was treated at room temperature with Pd(OH)2/C,(11.5 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was waihed with Et0H
(15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 2/3) to give Compound 19(41 mg, 88%). Electrospray MS [M-F1] 571.1.

(11'NH
NA CF, HN
'C F3 Compound 20 Step A:

(ji'NH
NH2 a. CHOCO,Et, NaBH(0A03, 11,00 CF, NA CF, HiCO sNA C F3 CICH,CH,CI
b. TMSN=C=0, CICH,CH,CI
CbzN CbzN CbzN
CF, CF, CF

Compound 2613 Compound 20a Compound 2013 NaBH(OAc)3 (81.4 mg, 0.384 mmol) was added at room temperature to a solution of Compound 26b (79.9 mg, 0.128 mmol), CHOCO2Et (37.8 IA
0.192 mmol, 45-50% in toluene), and 4 A molecular sieves (30 mg) in CICH2CH2CI (1.0 mL). The reaction mixture was stirred for 12 hours before it was diluted with Et0Ac (20 mL) and washed with aqueous NaHCO3 (10 mL).
The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product (91 mg, 0.128 mmol) was taken up in CICH2CH2CI (0.5 mL) and treated with TMSN=C=0 (2.5 mL). The reaction mixture was heated at 70 C for 72 hours before the solvent was removed under reduced pressure. The crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v 1/1) to give a mixture of Compound 20a and 20b, which was further purified by OD chiral HPLC to give pure Compound 20a (30 mg, 33%) and Compound 20b (25 mg, 28%).
Step 6:

(11'NH NH
H2C0¨%., CF, 11¨% CF, H2, Pd(OH)2/C, Et0H
CbzN HN=CF, CF, Compound 20a Compound 20 Compound 20a (23 mg, 0.0325 mmol) in Et0H (2.0 mL) was treated at room temperature with Pd(OH)2/C (4.6 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v 1/3 to 1/9) to give Compound 20 (14.3 mg, 77%). Electrospray MS [M-1-11, 574.3 PREPARATIVE EXAMPLE 21 and 22 HN LNH/ HN' I 0 CF, oF
Cr HN

w- 21 CF 40 ' H H 0 , Boc¨N N' CF, Boc--N OH CF, CbzN
PYBOP, DIEA CbzN 00 = 0 CF CF, 3 MeNH2, CH2C12 21a 21b Compound 21a (1.0 g, 1.4 mmol, 1.0 equiv) was dissolved in CH2Cl2 (16 mL) and the solution was cooled to 0 C. Diisopropylamine (0.54 g, 4.2 mmol, 3.0 equiv.) was added to the reaction mixture, followed by PYBOP
(0.88 g, 1.7 mmol, 1.2 equiv.), and the reaction mixture was stirred at 0 C
for 5 min., then warmed to room temperature. After 20 min., excess methyl amine (7.0 mL, 14 mmol, 10.0 equiv.) was added as a 2.0M solution in THF.
The flask became slightly warm, and was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (95/5 Et0Ac/Me0H eluent). Upon completion of the reaction, the reaction mixture was diluted with H20 and Et0Ac, the organic and aqueous layers were separated, and the organic layer was washed with brine, dried with Na2SO4, and concentrated to give a crude product (1.9 g) as white solid. Purification was carried out using BIOTAGE chromatography (1:1 to 2:1 Et0Ac/hexane) to give Compound 21b as a white solid (0.72 g, 72%).
Electrospray MS [M+1] 738.2.
H 0 z 0 Boc¨N N' CF, H2N
N" CP, CbzN 0 TFA, 0H3C12 CbzN
40 CF, CF
21b 21c Compound 21c (0.7 g, 0.95 mmol, 1.0 equiv) was dissolved in CH2Cl2 (10 mL) under a N2 atmosphere. To the reaction was added excess TFA (2.0 9,19.4 mmol, 20.0 equiv.), and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC
(1/1 Et0Ac/Me0H eluent), which indicated that some starting material was still present. Accordingly, 10.0 equiv. of TFA was added and the reaction mixture was allowed to stir for 3 h. Upon completion of the reaction, the reaction mixture was cooled to 0 C, quenched with saturated NaHCO3, and diluted with Et0Ac. The organic and aqueous layers were separated, and the organic layer was washed with brine, dried with Na2SO4, and concentrated to give Compound 21d (0.6 g, 99%) as a white foam.
Ni"BocOsa H2r4 CF, H NM
NH CF, BocNHNH2, ImCOlm CbzN = 0 40 THF ____ CbzN 0 SI
CF, 21c 21d Compound 21c (0.24 g, 0.38 mmol, 1.0 equiv) was dissolved in 5 mL
of anhydrous THE under a nitrogen atmosphere. The solution was cooled to 0 C. In a separate round-bottomed flask was combined carbonyldiimidazole (0.15 g, 0.90 mmol, 2.4 equiv) and tert-butyl carbazate (0.1 g, 0.76 mmol, 2.0 equiv) in anhydrous THF (2 mL). The solution was allowed to stir for 30 min and added via cannula to the solution of Compound 21c over 1 min. The cannula was rinsed with anhydrous THF (1 x 0.8 mL). The reaction mixture was heated to reflux until the starting material was consumed. The reaction mixture was then cooled to room temperature and concentrated under vacuum to afford a colorless foam. The crude mixture was purified using BIOTAGE chromatography (2%-5% Me0H/CH2C12) to give Compound 21d (0.22 g, 74%) as a white solid.
HFi , 13oc¨N,N, 0 2 0 H HN
H HN
NH CF, Ha in Dioxane NH' CF, CbzN
CH2C12 CbzN
CF, CF, 21e 21d Compound 21d (0.22 g, 0.28 mmo), 1 equiv) was dissolved in 15 mL
of anhydrous CH2Cl2 under a nitrogen atmosphere. The solution was cooled to 0 C. HCI (1.4 mL, 5.6 mmol, 20 equiv, 4 M solution in dioxane) was added and the solution was allowed to warm to room temperature and stirred overnight. The solution was cooled to 0 C and quenched with saturated NaHCO3 (5 mL) solution and diluted with Et0Ac. The organic and aqueous layers were separated and the organic layer was washed with brine (10 mL), and dried over Na2SO4. The organic layer was filtered and concentrated under vacuum to give a white solid. The crude mixture was purified using BIOTAGE
chromatography (5%-8% Me0H/CH2C12) to give Compound 21e (0.15 g, 79%) as a white solid.
H,Ne 0 H HN CF3 NHCHNH2 TN NH' CF, (SI
AcOH, DMF
CbzN 40 CbzN
= õ.0 C
CF, Fa 21e 21f Compound 21e (0.15 g, 0.22 mmol, 1.0 equiv) was dissolved in anhydrous DMF (1 mL). Foramidine acetate (0.126g, 1.2 mmol, 5.5 equiv.) followed by acetic acid (0.69 mL, 1.2 mmol, 5.5 equiv.) was added, and the reaction mixture was heated to 80 C for 30 min. Residual starting material was found by TLC analysis, and accordingly the reaction mixture was refluxed for an additional 6 h. The progress of the reaction was monitored by TLC (9/1 CH2C12/Me0H eluent). Upon completion of the reaction, the reaction mixture was cooled to room temperature, quenched with H20, and diluted with Et0Ac.
The organic and aqueous layers were separated and the organic layer was washed with brine, dried with Na2SO4, and concentrated to give a crude product (0.131 g) as white foam. Purification was carried out using BIOTAGE
chromatography (gradient of 100% CH2Cl2 to (95:5) Me0H) to give Compound 21f as a white solid (0.11g, 72%).
Electrospray MS [M+1] 706.4.
t HN1 0õ

0 NH CF, CF, N', NH. CF, 0 10%Pd/C, CF Me0H 40 CbzN 40 HN
CF, CF, ..õ 3 .'"22 21f Compound 21f (0.02 g, 0.028 mmol, 1.0 equiv.) was dissolved in dry Me0H (1.0 mL) and was treated with 10% Pd/C (40% wt.) followed by ammonium formate (0.09 g, 0.14 mmol, 5.0 equiv.) under an inert atmosphere. The reaction mixture was heated to reflux and was monitored by TLC (9/1 CH2C12/Me0H eluent). The reaction was completed in 1 hr. The reaction mixture was filtered through CELITE, washed using Et0Ac, and concentrated under vacuum. The resulting residue was taken up in Et0Ac, and washed with saturated NaHCO3, followed by brine and H20 to give a crude product (0.019 g) as solid film. Purification was carried out by BIOTAGE chromatography (gradient of 2% to 6% Me0H/CH2C12). The de-aired product was converted to the HCI salt to give a mixture of Compounds 21 and 22 (0.014 g) as a white solid.
HRMS (FAB) calculated for C26H28F6N302 (M+1)572.2096, found 572.2103.

e,NH
CF, CF, Compound 23 Step A:
0,N 0,N
CF, CF, NaBH4, Me0H, 0 C
CbzN CbzN
CF, CF, '11 Compound 23a Compound 23b NaBH4 (2.42 g, 64.1 mmol) was added in 4 portions to a solution of Compound 23a in Me0H (160 mL) at 0 C. The reaction mixture was stirred for 4 hours and the reaction temperature was slowly increased to rt. The reaction was quenched by the slow addition of saturated aqueous NH4CI
solution (50 mL). The reaction mixture was then diluted with Et0Ac (400 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly acidic.
The aqueous phase was extracted with Et0Ac (3 x 100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over MgSO4. After filtration and concentration, the crude product was passed through a short pad of silica gel (hexane/Et0Ac, v/v = 7/1). Solvent was removed under reduced pressure to give Compound 23b, 17.4 g (89%) as a light yellow syrup.
Step B:
0,N
NO
CF, , CF, 0,N,õ OH ,T
%..1 3 paraformaldehyde, TBAF

CbzN CbzN 0 II CbzN 0 CF, THF, CF, CF, Compound 23b Compound 23c Compound 23d TBAF (2.23 mL, 2.23 mmol, 1.0 M in THF) was added dropwise to a mixture of Compound 23b (9.1 g, 14.89 mmol) and paraformaldehyde (3.85 g) in THF (100 mL) at 0 C. The reaction mixture was stirred at 0 C for 8 hours before it was quenched with addition of saturated aqueous NH4CI solution (50 mL). The reaction mixture was then diluted with Et0Ac (250 mL) and the aqueous phase was extracted with Et0Ac (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE (CH2C12/Et0Ac, v/v = 100/0.5) to give Compound 23c (6.0 g, 63%) and 23d (2.34 g, 24%).
Step C:

CF, NH, CF, CbzN Zn, HOAc, 60 C
CF, ____________________________________ - CbzN n Compound 23c Compound 23e A mixture of Compound 23c (7.54 g, 11.76 mmol) and Zn dust (7.68 g, 117.6 mmol) in HOAc (120 mL) was heated at 60 C for 2 hours. The reaction mixture was cooled down and filtered through a short pad of CELITE and the residue was washed with Et0H (50 mL). Solvent was removed under reduced pressure and the residue was taken up in Et0Ac (250 mL) and washed with NaOH solution (50 mL, 4.0 N). The aqueous phase was extracted with Et0Ac (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 1/3 and Et0Ac/Me0H, v/v = 10/1) to give Compound 23e (6.4 g, 89%).
Step D:

CF, CF, BnBr, (NH4LHSO4, NaOH,THF
CbzN CbzN
CF, CF, Compound 23e Compound 231 BnBr (0.668 mL, 5.58 mmol) was added at rt to a vigorously stirring mixture of Compound 23e (3.1 g, 5.07 mmol) and Bu4NHSO4 (0.334 g, 1.014 mmol) in THF (20 mL) and aqueous NaOH solution (20 mL, 50 wt%). The reaction mixture was stirred at room temperature for 12 hours before it was diluted with Et0Ac (250 mL) and washed with water (100 mL). The aqueous phase was extracted with Et0Ac (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE
chromatography (hexane/Et0Ac, v/v = 1/3 to 1/7) to give Compound 23f (2.8 g, 79%).
Step E:
Et N, NHNH
\=N¨NHCO CH3 Et0H
2 CF, a, , 31c Bn0--', NA CF3 b. NaOCH3, NleCH, 80 C
CbzN
CF3 CbzN c Compound 23f Compound 23g A solution of Compound 23f (2.72 g, 3.88 mmol) and reagent 31c (i.e., N-ethoxymethylene-hydrazine carboxylic acid methyl ester) (2.83 g, 19.4 mmol) in Et0H (15 mL) was heated at 60 C for 18 hours. The reaction mixture was diluted with Me0H (15 mL) and then treated with NaOCH3 (7.0 mL, 38.8 , mmol, 30% in Me0H). The resulting i=eaction mixture was heated at 80 C for 4 hours before it was cooled to room temperature. The reaction mixture was diluted with Et0Ac (200 mL) and aqueous NH4CI solution (75 mL). The aqueous phase was extracted with Et0Ac (3 x 50 mL). The combined organic layers were washed with water (50 mL), brine (100 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 2.5/1 to 1/1) to give Compound 23g (2.54 g, 85%).
Step F:

('N'NHN,NH
CF, CF, BC13, CI-1,C12, -78 C
CbzN 40 CbzN
CF, CF, =
=
Compound 239 Compound 23h BCI3 (3.26 mL, 3.26 mmol, 1.0 M in hexane) was added dropwise to a stirring solution of Compound 23g (0.502 g, 0.653 mmol) in CH2Cl2 (45 mL) at -78 C. The reaction was quenched in 1 hour by the addition of aqueous NaHCO3 solution (50 mL) at -78 C. The mixture was diluted with Et0Ac (100 mL) and vigorously stirred at room temperature for 2 hours. The aqueous phase was extracted with Et0Ac (3 x 30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE
chromatography (hexane/Et0Ac, v/v = 1/3 to 1/9) to give Compound 23h (0.39 g, 91%).
Step G:
cANHN,NH
CF, HO. CF, H2, Pd(OH)2/C, Et0H
CbzN

, CF, =
Compound 23h Compound 23 Compound 23h (100 mg,-0:152-mmo1) in Et0H (5.0 mL) was treated at room temperature with Pd(OH)2/C (20 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction mixture was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 1/7) to give Compound 23 (68 mg, 82%). Electrospray MS [M+1r 545.1.

N OH
H
CF, HN
CF, Example 24 N'N1) jOH
CF, 1)03, CH2C12,-78C CF, 2) Et0H, NaBH4 CbzN cr, 3) PCKOHL/C, H2 HN 0 CF, (63%) 31g Example 24 A solution of Compound 31g (83.3 mg, 0.12 mmol, 1.0 equiv.) in anhydrous dichloromethane (4 mL) was cooled to -78 C. Then 03 was bubbled through the solution until the solution turned blue. The solution was then purged with N2 to remove excess 03, and the reaction mixture was concentrated to dryness. The resulting residue was then taken up in ethanol (2 mL), and treated with sodium borohydride (46 mg, 1.2 mmol, 10 equiv.).
The reaction mixture was stirred at room temperature until TLC (50%
Et0Ac/hexanes) showed that the starting material was completely consumed.
The reaction mixture was then concentrated to dryness. The residue was dissolved in absolute ethanol (4 mL) and treated with Pd(OH)2/C (80 mg, 20 wt%, 0.11 mmol, 0.88 equiv.) before hydrogenating with a hydrogen balloon.
The reaction mixture was stirred at room temp_erature until TLC.(5 /0 Me0H/CH2C12) showed that the starting material was completely consumed.
The reaction mixture was again concentrated to dryness. The residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the aqueous and organic layers separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated to give the crude product, which was purified using Prep-TLC (Me0H/CH2C12 =5%) to give pure Compound 24 (42 mg, yield 63%). MS [M+1]+ 559.1.

CF, CF, compound 25 N N __ CF, CF, Pd(OH)2/C, CbzN CF Et0H __ HN 40 , CF, (84%) 41, 31g compound 25 To a solution of Compound 31g (83.3 mg, 0.12 mmol, 1.0 equiv.) in absolute ethanol (3 mL) was added Pd(OH)2/C (20 mg, 20 wt%, 0.028 mmol, 0.88 equiv.) before hydrogenating with a hydrogen balloon. The reaction mixture was stirred at room temperature until TLC (50% Et0Ac/hexanes) showed that starting material was completely consumed. The reaction mixture was then concentrated to dryness. The resulting residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the aqueous and organic layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified using Prep-TLC (50% Et0Ac/hexanes) to give pure Compound 25 (15 mg, yield 84%). MS [M-1-1]4 557.1.

N
N40 CF, HN 140 CF, Compound 26 Step A:
HO NH2 CF, NHBoc HO CF, Boc.20, NEt,, dioxane CbzN gp CF, _________________________________________ CbzN

Compound 26a Compound 26b Et3N (0.129 mL, 0.93 mmol) was added to a solution of Compound 26a (0.472 g, 0.77 mmol) and Boc20 (0.168 g, 0.77 mmol) in dioxane (3.0 mL) at room temperature. The resulting solution was stirred for 8 hours before it was diluted with EtOAc (50 mL). The organic phase was washed with 0.5 N
HCI (10 mL). The aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over Mg SO4. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 1/1) to give Compound 26b (0.465 g, 85%).
Step B:
NHBoc NHBoc HO CF, H3C0 CF, CH31, (NH4)4HB04, NaOH, THF
CbzN 411 CbzN
CF, CF, Compound 26b Compound 26c CH3I (0.372 mL, 5.98 mmol) was added at rt to a vigorously stirring mixture of Compound 26b (0.425 g, 0.598 mmol) and Bu4NHSO4 (40.6 mg, irITHF (5-.0 mL) and aqueous NaOH solution (5.0 mL, 50 wt%).
The reaction mixture was stirred at room temperature for 12 hours before it was diluted with Et0Ac (50 mL) and washed with water (15 mL). The aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE
chromatography (hexane/Et0Ac, v/v = 5/1) to give Compound 26c (0.345 g, 80%).

Step C:
a. TFA
N. N.

Et0 NH, H,C0 CF, b.\=N¨NHco,CH, Et0H
NA CF, H3C0 PA CF, 31c 40 c NaOCH,, Me0H, 80 C
CbzN CbzN CbzN
CF, CF 3 CF, Compound 26c Compound Compound 26e 26d A solution of Compound 26c (0.345 g, 0.476 mmol) in TFA (3.0 mL) was stirred at room temperature for 20 minutes before the solvent was removed under reduced pressure. The residue was taken up in Et0Ac (50 mL) and washed with NaOH solution (4.0 N, 15 mL). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude amine (0.29 g, 0.464 mmol) was dissolved in Et0H
(3.0 mL) and treated with reagent 31c (0.4.6 g, 2.78 mmol). The resulting solution was heated at 60 C for 18 hours. The reaction mixture was diluted with Me0H (3.0 mL) and then treated with NaOCH3 (0.672 mL, 3.712 mmol, 30% in Me0H). The resulting reaction mixture was heated at 80 C for 4 hours before it was cooled to room temperature. The system was diluted with addition of Et0Ac (50 mL) and aqueous NH4CI solution (15 mL). The aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE
chromatography (hexane/Et0Ac, v/v 1/3) to give a mixture of Compounds 26d and 26e (0.275 g, 83% for 3 steps) which were separated with OD chiral HPLC (hexane/isopropanol v/v = 95/5) to give pure Compounds 26d and 26e.
Step D:

(N. NHN
NA CF, H3CO. N40 CF, Pd(OH)2/C, Et01-1 CbzN 40 HN 40 CF, CF, Compound 26d Compound 26 Compound 26d (38 mg, 0.0548 mmol) in Et0H (3.0 ririL) was treated at room temperature with Pd(OH)2/C (7.6 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v 1/4) to give Compound 26 (25 mg, 82%). Electrospray MS [WET 559.1.

NH
H3C0 .=NA CF, CbzN
CF, Compound 27 Step A:
N, NH
NH
H3C0 CF, H3C0 CF, H2, Pd(OH)2/C, Et0H
CbzN 001 CbzN 0 CF, CF, Compound 26e Compound 27 Compound 26e (41 mg, 0.0592 mmol) in Et0H (3.0 mL) was treated at room temperature with Pd(OH)2/C (8.2 mg, 10 wt%) and was hydrogenated using a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). Solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 1/4) to give Compound 27 (26 mg, 79%). Electrospray MS [M-1-1]+ 559.1.

rsLC) F,C
,2 CF, Compound 28 Step A:
cr-r- . F3c CF, :
Bo-a-methyl alanine HN
HN ,n . CF, ,v CF, HATU, EDC, DIEA
= Fit' 1 0 Compound 44b Compound 28a In a 25 mL round-bottomed flask, Compound 44b (0.2 g, 0.45 mmol, 1.0 equiv) was dissolved in DMF (5.0 mL). HATU (0.342 g, 0.90 mmol, 2.0 equiv), EDC (0.172 g, 0.90 mmol, 2.0 equiv), and D1EA (0.118 mL, 0,68 mmol, 1.5 equiv) were added. The reaction mixture was cooled to 0 C and Boc-a-methyl alanine (0.109 g, 0.54 mmol, 1.2 equiv) was added. The reaction mixture was allowed to stir overnight. The reaction mixture was then quenched with saturated NaHCO3 (5 mL), diluted with Et0Ac (10 mL), and extracted with Et0Ac (2 x 5 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, and concentrated. The resulting residue was purified by preparative TLC (9/1 hexanes/Et0Ac) to give 0.12 g (43%) of Compound 28a.
Step B:

HNI74NHEtocF3C

TFA, DCM
o CF3 CP, HN HN
Compound 28a Compound 28b Compound 28b was prepared by a method similar to that the compound 45c, described below, in which a DCM solution of Compound 28a was reacted with TEA to remove the Boc protecting group.
Step C:

( Hi NH, F3C
N

HC(0M03 n CF3 HN =õ/- CH3CO2H HN 40 cF, =
Compound 28b Compound 28 In a 10 mL round-bottomed flask, compound 28b (0.050 g, 0.094 mmol, 1.0 equiv) was dissolved in toluene (1 mL), and then trimethylorthoformate (0.012 mL, 0.113 mmol, 1.2 equiv) and 1 drop of acetic acid were added. The solution was heated at 60 C. The reaction mixture was allowed to stir for over 48 hours. The reaction mixture was then taken up in Et0Ac (5 mL) and washed with saturated NaHCO3 (5 mL). The organic layer was washed with brine (5 mL), dried over MgSO4, and concentrated. The crude product was purified by preparative TLC (Et0Ac) to yield 0.010 g of Compound 28. HRMS calculated for C27H23F6N302 (M+H) 542.2242, found 542.2222.

cF, HN
CF, Example 29 (10 H
N. I N I
,s¨0O21-1 CF, cF, 1) Et0C(0)C1, Et,N
NH3, CH2C12 CbzN FIN
CF, 2) Pd(OFI)21C, H2 CF, (57% for 2 steps) Example 29 A solution of Compound 31h (39 mg, 0.055 mmol, 1.0 equiv.) in anhydrous dichloromethane (1 mL) was cooled to -20 C. Then triethylamine (10 mL, 0.069 mmol, 1.25 equiv.) and ethyl chloroformate (6.5 mL, 0.066 mmol, 1.2 equiv.) were added. The resulting pale green solution was stirred at -15 C for 30 minutes. Ammonia gas was bubbled through the solution for 20 minutes. TLC (Et0Ac) indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate, washed sequentially with 1N
HU (1 mL), saturated sodium carbonate aqueous solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was dissolved in absolute ethanol (6 mL), to which was added Pd(OH)2/C (17 mg, 20 wt%, 0.024 mmol, 0.43 equiv.) before attaching a hydrogen balloon to the reaction flask. The reaction mixture was stirred at room temperature until TLC (5% Me0H/Et0Ac) showed that the starting material was completely consumed. The reaction mixture was concentrated to dryness, and the residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, and the organic and aqueous layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified using Prep-TLC (5% Me0H/Et0Ac) to give pure Example 29 (18 mg, yield 57%).
MS [M+1]+ 572.1.

CF
HN

compound 30 Step 1:

\;¨N CF, HATU, MeONH2MeCI
CbzN o CbzN
CF3 DIEA, DMF CF3 (43.6%) 31h 30a To a solution of Compound 31h (450 mg, 0.64 mmol, 1.0 equiv.) in anhydrous DMF (3.5 mL), was added, sequentially, HATU (290.5 mg, 0.764 mmol, 1.2 equiv.), N,N-dimethylamine hydrochloride salt (99 mg, 1.01 mmol, 1.6 equiv.) and diisopropyl ethylamine (0.50 4, 2.87 mmol, 4.5 equiv.). The resulting orange solution was stirred at room temperature until TLC (5%
Me0H/Et0Ac) showed that starting material was completely consumed. The reaction mixture was poured into dichloromethane (200 mL), washed sequentially with half-saturated citric acid aqueous solution, saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified using BIOTAGE chromatography (Et0Ac/Hexane =3:1) to give Compound 30a as a brown solid (208 mg, yield 43.6%).
Step 2:

N,zr. "N¨OH CF3 NjµLr CF, = ¨10 MeMg13r, THF
CbzN . CbzN ____________________________________ 0 40 =
30a 30b Methylmagnesium bromide (1.65 mL, 1.0 M in t-butylether, 1.65 mmol, 6.0 equiv.) was added dropwise to a solution of Compound 30a (206 mg, 0.275 mmol, 1.0 equiv.) in anhydrous THF (3 mL). TLC (Et0Ac) showed that the starting material was totally gone after the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with ethyl acetate, quenched with a saturated aqueous NH4CI solution, and extracted with Et0Ac. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, Compound 30b.
Compound 30b was used in the next step without purification.
Step3:

N 14r _________________ N11 CF, CF3 Fd(OH)3/C, H2 CbzN 0 HN

(96% from 30a) 30b 30 Using the same procedure as that of Example 31, Step 6, the crude Compound 30b was hydrogenated to give pure Example 30 (150 mg, yield 95.6% from Compound 30a). MS [M+1r 571.1.

N NII) ,s¨0O3Me CF3 Step 1:
88 C Et0 H3NNHC(0)0CH3 + (Et0)3CH
(>55%) sC(0)0CH3 31a 31 b 31c Compound 31b (32 mL) was added to a solution of Compound 31a (1.09, 11.1 mmol, 1.0 equiv.) in triethylorthoformate. The solution was heated at 88 C for 36 hours, and then concentrated to dryness under vacuum.
The resulting residue was recrystallized from Et0Ac, to give Compound 31c (0.94 g, yield 58%).

Step 2:
CF, 02 CbzN le] N CF, CbzN
40 1) me0yO i, CF, CbzN o40 CF, Pd(PPh3)4 CF, CF, 2) HPLC separation II
23b 31d 31e To a solution of Compound 23b (2.5 g, 4.1 mmol) in THE (20 mL) was added allylmethylcarbonate (0.465 ml, 8.2 mmol), and Pd(PPh3)4 (236 mg, 0.205 mmol). The reaction vessel was purged three times with nitrogen, and then the solution was allowed to stir for 16 hours. The solvent was then removed and the residue was filtered through a short silica column using 20%
EtOAC /hexanes as eluent. The filtrate was concentrated and Compounds 31d and 31e were separated using prep-HPLC. MS [M+1] 651.1 for both compounds.
Step 3:
02N CF, H2N CF, Zn/ HOAc CbzN 410 _____ CbzN 0 40 CF CF, 111 (82%) 31d 31f A round-bottomed flask was charged with Compound 31d (3.84 g, 5.90 mmol, 1.0 equiv.) and glacial acetic acid (20 mL). To the resulting yellowish solution at 0 C was added as several small portions of Zinc dust (3.86 g, 59.0 mmol, 10 equiv.). The reaction mixture was stirred at room temperature for 6 hours until TLC (30% Et0Ac/hexane) showed that the starting material Compound 31d was totally consumed. The reaction mixture was then diluted with ethyl acetate, and passed through a CELITE pad in a funnel. The CELITE pad was thoroughly washed with ethyl acetate, and the combined with the filtrate. The filtrate was concentrated to provide a crude product, which was purified using BIOTAGE chromatography (30%

Et0Ac/hexanes) to give a pure colorless oil product, Compound 31f (3 g, yield 81.9%).
EtO
112N CF3 , `=N-NH
e co2me CF3 31c Et0H
CUN , cb. o40 CF3 1> Me0H, Me0Na, 70 C CF3 311 (p60%) 31g To a solution of Compound 31f (33.4 mg, 0.054 mmol, 1.0 equiv.) in ethanol (0.4 mL) was treated with reagent 31c (67.5 mg, 0.46 mmol, 5 equiv.) and stirred at room temperature overnight. It was then diluted with anhydrous methanol (1 mL) and treated with sodium methoxide, then heated at 88 C until TLC (Et0Ac) showed only product. It was concentrated to dryness, and then taken up into ethyl acetate, washed with saturated sodium bicarbonate solution and the layers were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to get the crude product, which was purified via BIOTAGE chromatography (25-40% Et0Ac/hexanes) to get pure compound 31g (22.4 mg, yield >60%).
Step 4:
.1:1 N¨t ) CF s¨0O2H CF, 1)03, CH,C12, Me0H. -78C
C
CbzN bzN
CF 2) H203, HCO211 (90.6%) 31g 31h Compound 31g (306 mg, 0.44 mmol, 1.0 equiv.) was dissolved in anhydrous dichloromethane (5 mL). The resulting colorless solution was cooled to -78 C, then 03 was bubbled through until the solution turned purple.
The solution was then purged with N2 to remove excess 03. The solution was then concentrated to dryness. The resulting white foam was dissolved in formic acid (1.5 mL) and treated with hydrogen peroxide (1.5 mL, 30%
aqueous solution) to form a white suspension, which was heated to 80 C
overnight. LCMS analysis showed only the product peak. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate and washed with half saturated Na2S203 aqueous solution. The resulting two layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the Compound 31h (284.2 mg, yield 90.6%).
Compound 31h was used in the next step without purification.
Step 5:
r Nt CF, ¨COMe CF, CbzN010 CbzN
CFBenzene CF, , 11/ Me0H
3m 31i To a solution of Compound 31h (104 mg, 0.147 mmol, 1.0 equiv.) in benzene (4 mL) and methanol (1 mL), was added dropwise a 2.0M solution of trimethylsilyl diazomethane in hexanes (88 p.L, 0.177 mmol, 1.2 equiv.). TLC
(10% Me0H/CH2C12) showed that the starting material was gone completely after stirring the reaction mixture at room temperature for 30 minutes. The solvent was removed to give the crude product, which was used in the next step without purification.
Step 6:
H
r r s¨0O2Me CF, õ,--0O2Me CF, Pd(OH)2/C
CbzN 0CF, HN
CF, H2, EtOH
311 (65% from 31g ) compound 31 The crude product from Step 5, Compound 311, was dissolved in absolute ethanol (4.5 mL). To this solution was added Pd(OH)2/C (46.7 mg, 20 wt%, 0.067 mmol, 0.45 equiv.), and then the reaction mixture was hydrogenated with a hydrogen balloon. The hydrogenation reaction was stopped when TLC (10% Me0H/CH2C12) showed that the starting material was consumed. The diluted reaction mixture was carefully passed through a CELITE packed funnel, and the CELITE pad was washed thoroughly with methanol. The filtrate was concentrated to dryness. The resulting residue was purified by prep-TLC (10% Me0H/CH2C12) to give the pure Compound 31(56.2 mg, yield 65% from Compound 31g), MS [M+1]+ 587.1.

Ctoctsi CF, HN

Step 1:
ct H,N .,,CN CF, ,0 (I C N CF, CbzN CbzN n CF, Et3N, (CH3),C13 CF
Reflux 42b 323 In a 25 ml round-bottomed flask, Compound 42b (0.142 g, 0.23 mmol, 1.0 equiv) was taken up in 3 mL of dichloroethane under a N2 atmosphere and the reaction mixture was treated with Et3N (0Ø48 ml, 0.34 mmol, 1.5 equiv) followed by 3-chlorosulfonyl propyl chloride (0.037 ml, 0.3 mmol, 1.2 equiv).
The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (60:40 Et0Ac/hexane) and MS, which indicated no desired product was formed. Accordingly, the reaction mixture was then heated to reflux. After one hour of heating the reaction was complete. The reaction mixture was then cooled and diluted with CH2Cl2, and quenched with IN HCI. The organic layer was dried over Na2SO4 and concentrated to give crude Compound 32a (0.11 g), which was used in the next step without further purification.
Step 2:
CI
H
or,s-N .,,CN CF, cro,. CF, 3 DBU, DMF
CbzN CbzN
=
CF, CF

32a 32b In a flame dried 15 ml round-bottomed flask, Compound 32a (0.11 g, 0.23 mmol, 1.0 equiv) was taken up in dry DMF. To this reaction mixture, 1,8-diazabicyclo[5.4.0jundec-7ene (0.044 g, 0.29 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC (30:70 Et0Ac/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with Et0Ac and quenched with H20. The organic layer was dried over Na2SO4 and concentrated to give crude Compound 32b (0.1g). Purification was carried out using 1310TAGE chromatography (30/70 Et0Ac/hexane) to give purified Compound 32b (0.072g).
Electrospray MS [M+1] 710.2.
Step 3:
o 9 \-11 CN CF, 20% Pc1OH, \A ,,CN CF, Me 1-1, H2(9) CbzN CF HN
CF, , IP32b 32 Compound 32b (0.072 g, 0.1 mmol, 1.0 equiv) was dissolved in dry Me0H (1.5 ml) and was treated with 20% Pd(OH)2 (60% wt.) under an inert atmosphere. The reaction was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 Et0Ac/hexane).

The reaction was completed in 45 min, and was filtered through CELITE, washed with Et0Ac, and concentrated to give a crude product. The crude product was purified using preparative chromatography (60/40 Et0Ac/hexane) to give Compound 32 (0.04g, 70%).
Electrospray MS [M+1]576.2.
HRMS (FAB) calculated for C26H28F6N302(M+1) 576.1756, found 576.1764.

KI õcN CF, Example 33 Step 1:
H2N ,CN CF, cr CF, CbzN 40 Et3N, CH,CI, CbzN 0 CF, CF

42b 33a In a 25 ml round-bottomed flask, Compound 42b (0.322 g, 0.53 mmol, 1.0 equiv) was taken up in 5 ml of CH2Cl2and the reaction mixture was cooled to 0 C in an ice bath. Et3N (0.111 mL, 0.79 mmol, 1.5 equiv) followed by 4-chlorobutyryLchloride (0.072 .ml, 0.64 mmol1-.1-.2-equiv)_was-then added-to the reaction mixture, which was slowly warmed to room temperature and stirred for 14 his. The progress of the reaction was monitored by TLC (60:40 Et0Ac/hexane eluent) and MS. Upon completion of the reaction, the reaction mixture was diluted with CH2Cl2 and quenched with saturated NaHCO3 followed by brine. The organic layer was dried over Na2SO4 and concentrated to give crude Compound 33a (0.32 g), which was used in the next step without further purification.

Step 2:
CI
;CN CF, I!! ,CN CF, 8 60% NaH, THF
CbzN 40 CF, CbzN (-) In a flame dried 25 ml round-bottomed flask, Compound 33a (0.32 g, 0.45 mmol, 1.0 equiv) was taken up in dry THE. To this solution, 60% NaH
(0.025 g, 0.68 mmo(, 1.5 equiv) was added, and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by TLC (60:40 Et0Ac/hexane) and MS. Upon completion of the reaction, the reaction mixture was diluted with Et0Ac and quenched with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give Compound 33b (0.4 g), in the form of a yellow oil, which was used in the next step without further purification.
Step 3:
,CN CF, 20% Pd0H, N CN C
Me0H, H2(g) CbzN 40 RN
CF, CF, 33b compound 33 Compound 33b (0.4 g, 0.59 mmol, 1.0 equiv) was dissolved in dry Me0H (4.0 mL) and was treated with 20% Pd(OH)2 (60% wt.) under an inert atmosphere. The reaction was hydrogenated at atmospheric pressure and the progress of the reaction was monitored by TLC (40:60 Et0Ac/hexane eluent). The reaction was completed in 45 min, was filtered through CELITE
and washed using Et0Ac and concentrated to give a crude product.
Purification of the crude product was carried out using BIOTAGE
chromatography (60/40 Et0Ac/hexane) to give Compound 33 (0.18 g, 59%).
HRMS (FAB) calculated for C26H28F6N302(M+1) 540.2086, found 540.2078.

N, CN CN CF3 HN

Example 34 Step 1:
H2Nõ, CN CF3 CbzN 40 .F3 Et3N, CH2C1, CbzN CF

42c 34a In a 25 ml round-bottomed flask, Compound 42c (0.23 g, 0.38 mmol, 1.0 equiv) was taken up in 3 mL of CH2Cl2, and the reaction mixture was cooled to 0 C in an ice bath. Et3N (0.079 ml, 0.57 mmol, 1.5 equiv) followed 10 by 4-chlorobutyryl chloride (0.051 ml, 0.45 rnmol, 1.2 equiv) was then added to the reaction mixture, which was slowly warmed to room temperature and was stirred for 14 hrs. The progress of the reaction was monitored by TLC
(60:40 Et0Ac/hexane eluent) and MS. Upon completion of the reaction, the reaction mixture was diluted with CH2Cl2 and quenched with saturated 15 NaHCO3 followed by brine. The organic layer was dried over Na2SO4 and concentrated to give crude Compound 34a (0.23 g), which was used in the next step without further purification.
Step 2:
FNIõ CN CF, CN CF, 0 60% NaH, CbzN 010 .F3 THF CbzN
34a 34b In a flame dried 25 ml round-bottomed flask, Compound 34a (0.23 g, 0.38 mmol, 1.0 equiv) was taken up in dry THF (1 mL). To this reaction mixture, 60% NaH (0.022 g, 0.57 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 2 hrs. The progress of the reaction was monitored by TLC (60:40 Et0Ac/hexane eluent) and MS.
Upon completion of the reaction, the reaction mixture was diluted with Et0Ac and quenched with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give Compound 34b (0.21 g) in the form of a yellow oil, which was used in the next step without further purification.
Electrospray MS [M+1] 674.2.
Step 3:
ON CF, 20% NOR \ CN OF, Me0H, 143(9) ClazN HN
CF, CF, 34b 34 Compound 34b (0.21 g, 0.31 mmol, 1.0 equiv) was dissolved in dry Me0H (2.0 mL) and was treated with 20% Pd(OH)2 (40% wt.) under an inert atmosphere. The reaction mixture was hydrogenated at atmospheric pressure and the progress of the hydrogenation was monitored by TLC (40:60 Et0Ac/hexane eluent). After 45 min, the reaction mixture was filtered through CELITE, washed with Et0Ac, and concentrated to give a crude product. The crude product was purified using BIOTAGE chromatography (60/40 Et0Ac/
hexane), to give Compound 34 (0.10 g, 59%).
HRMS (FAB) calculated for C26H28F6N302(M+1)540.2086, found 540.2078.

N.
(.> NH
NC .2N40 CF, MN
CF, Compound 35 HO NO2 CF, HO =IsjH2 CF, CbzN Zn, HOAc, 60 C
CF, ____________________________________ . CbzN

Compound 23d Compound 35a Compound 35 was prepared using a procedure similar to procedure for preparing Compound 23e in Example 23.
Bn0 PH' CF, HO .,Ni-12 CF, BnBr, (NH4)4HS0,, NaOH,THF
CbzN CbzN 1110 CF3 CF, Compound 35a Compound 35b Likewise, Compound 35b was prepared by a procedure similar to the procedure used to prepare Compound 23f in Example 23.
Et0 Bn0 NH2CF, a. \=N¨NHCO2CH3 , Et0HN,NH
31c Bn0j44 CF, = 0 CbzN 01110 b. NaOCH,. Me0H, 60 C

CF, CbzN

Compound 35b Compound 35c Compound 35c was prepared by a procedure similar to the procedure used to prepare Compound 23g in Example 23.

c.,ANH c%N.NH
N-io CF, 13n0-',.. N40 CF, Pd(OH)2. H2 CbzN _______________________________________ _ HN .,,,0 40 CF, Me0H CF, e =
Compound 35c Compound 35d Compound 35d was prepared by a procedure similar to the procedure for preparing Compound 23 in Example 23.
N, f? NH
Bn0,. N---c) CF3 HO, NA CF, 80,, DCM

=,õ..,0 78 C HN (-) ..,, CF, '--- IS CF, -. 4, Compound 35d Compound 35e Compound 35e was prepared by a procedure similar to the procedure for preparing Compound 23h in Example 23.
("-*N,NH
.
H N,NH
HO PI-% CF, 0 ..:N-io CF, HN . 0 40 Dess-Martin penodinane CF, __________________________________________ , HN .õ,....,0 40 = II CF, ' Compound 35e Compound 35f Compound 35f was preparing by a procedure similar to the procedure _fo_r_preparing_C.o.mp.o.und 42e. in ExampleA2. _______... . _....._ _ .
H (%N..N1-1 0 ?NA CF, HO,N.....p.__.$0 cF
NH,OH.HCI, Na0Ac HN . 0 0 . 0 0 CF, Et HN 0H CF, II *
. Compound 36f Compound 35g Compound 35g was prepared by a procedure similar to the procedure for preparing Compound 42g in Example 42.
N.
NH cs,NNH
11(:)µIg¨ CF3 NC 1\14 CF3 1,1 '-oxalyldiimidazo!e = 0 :
HN o HN
CF3 Benzene CF, Compound 35g Compound 35 Compound 35 was prepared by a procedure similar to the procedure for preparing Compound 42 in Example 42. HRMS calculated for C25H23F6N502 (M+H) 540.1834, found 540.1822.

NHSO2Me CF3 HN tio CF, Compound 36 Step A:
NC, NH2 CF3 NO,, NHSONe OF, MsCI, TEA
CbzN 010 CbzN

Compound 42b Compound 362 Compound 36a was prepared by a procedure similar to the procedure for preparing Compound 47 in Example 47.
Step NC, i9n.1/2me c3 NC, NHSO2Me H2, Pd(OH)2 CbzN 0 le HN 0 el CF, Me0H CF, Compound 36a Compound 36 Compound 36 was prepared by a procedure similar to the procedure for preparing Compound 23 in Example 23. HRMS calculated for C24H25F6N1303S (M+H) 550.1599, found 550.1603.

NC PHSO2Me CF, HN 0 el CF, Compound 37 Step A:
NC ,NH 2 CF, NC PHSO2Me MsCI, TEA
CbzN o CbzN
CF, CF3 Compound 42b Compound 37a Compound 37a was prepared by a procedure similar to the procedure for preparing compound 47 in Example 47.
.Step_B:_ NC ,4I-1602Me 0F3 NC ,NHSO2Me CF3 H2, Pd(OH)2 CbzN 4011 CF, Me0H CF, Compound 37a Compound 37 Compound 37 was prepared using a procedure similar to the procedure for preparing Compound 23 in Example 23. HRMS calculated for C24F125F6N3038 (M+H) 550.1599, found 550.1603.

CF3 HNI-4( 1) 03, TBAI **
2) NI-120N, Na0Ac CbzN 410 CbzN 40 CF CF, 3) (11n)2 C0 31g 38a Step 1:
To a solution of Compound 31g (640 mg, 0.93 mmol) in 10 mL CH2Cl2 maintained at -78 C was bubbled 03 gas until the reaction mixture turn blue.
The reaction mixture was then purged with nitrogen until it became colorless.
TBAI (412 mg, 1.11 mmol) was then added and the reaction mixture was stirred at 20 C for 2h. The reaction mixture was diluted with diethyl ether, washed with saturated aqueous Na2S203, water and brine, and the dried and concentrated. The resulting residue was dissolved in Et0H (22 mL) and Na0Ac (262.7 mg, 3.2 mmol) and hydroxylamine hydrochloride salt (222 mg, 3.2 mmol) were added, and the mixture was stirred overnight. The reaction mixture was then concentrated and the residue was partitioned between 20 mL Et0Ac and water. The organic layer was dried and concentrated. The crude intermediate was dissolved in toluene (6.8 mL) followed by the addition of 1,1'-oxallyldiimidazole (165 mg, 1.8 mmol) and the mixture was heated at 80 C for 2h. After cooling the reaction mixture to 23 C, the toluene solution was loaded to a silica gel column and eluted with 20-100% Et0Ac/hexanes to give product Compound 38a. MS [M+1] 688.1.

, FIN:: 4 õ--...4,-/N
4,0 CF CF, i.i ...õ/N =
CbzN ..õ70 el Pd(OH)21C, H2 CbzN .,,,,o 41) CF, CP, li le 38a compound 38 Step 2:
Using a procedure similar to that of Example 31, Step 6, Compound 38a was hydrogenated to give Compound 38. MS [M+1]+ 554.1.
PREPARATIVE EXAMPLE 39 and 40 NC pH2 , CF, HN el HN 0 OP
CF, ',,.= CF, . li Compound 39 Compound 40 Step A:
NH' NC,,. NH, CF, CF, _ -\ _________________ , CF, HN
ii. CF, Compound 42b 112, Pd(OH)2 Compound 40 4. Me0H
+
NC pH. CF, NC NH, CF, CbzN 0 40 HN 0 0 CF, =,, CF, Compound 42c Compound 39 Compounds 39 and 40 were prepared using a procedure similar to the procedure for preparing Compound 38. HRMS calculated for C23H23F6N30 (M+H) 472.1824, found 472.1820.

NC,. NHCONH2 0F3 HN
CF, Compound 41 Step A:
NC,, NH2 CF, NC, NHCONH2 CF, TMSNC
CbzN so CbzN
CF, DCE CF, Compound 426 Compound 41a In a 25 mL round-bottomed flask Compound 42b (0.15 g, 0.248 mmol, 1.0 equiv) was dissolved in 6 mL of DCE. Trimethylsilyl isocyanate (0.51 mL, 3.72 mmol, 15.0 equiv) was added and the reaction mixture was refluxed at 80 C overnight. The reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous phase was extracted with Et0Ac (2 x 10 mL). The organic layers were washed with brine (5 mL), dried over MgSO4, and concentrated. The crude product was purified by preparative TLC
(1:1 Et0Ac:hexanes) to yield 0.060 g (37%) of Compound 41a.
Step B:
NCõ. NHCONH2 CF, NC. NHCONH2 CF, H,, Pd(OH)2 CbzN 411 HN 0 40 CF, Me0H CF, Compound 41a Compound 41 aompound-41-was-prepared-by-a-pro-cedure-similarto procedure for preparing Compound 23 in Example 23. HRMS calculated for C24H24F6N402 (M+H) 515.1882, found 515.1874.

NH

Compound 42 Step A:

CF, NH2 C NC ,PH2 CF3 NC, F, NaCN, NH4CI, NH3.F120 CbzN
CbzN C CF, 111.
CF3 CbzN
CF, =
=
Compound 41a 42b Compound 42c Compound 41a (6.87 g, 11.86 mmol) in Et0H (7 mL) was added to a solution of NaCN (0.767 g), NH4CI (0.889 g) and NH3+120 (3.84 mL) in Et0H
(7.0 mi.) and water (7.0 mL) at room temperature in a sealed tube. The sealed tube was then heated at 60 C for 12 hours before it was cooled down to room temperature. The reaction mixture was diluted with Et0Ac (200 mL) and washed with water (50 mL). The aqueous phase was extracted with Et0Ac (3 x 30 mL). The combined organic layers were washed with brine (30 mL), and dried over Mg SO4. After filtration and concentration, the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 7/2 to 5/2) to give Compound 42b (2.6 g, 36%) and Compound 42c (1.8 g, 25%).
Step B:

NC.,. NH2 CF3 COC12/NaHCO3 then NH2NHC(0)H/Py NH CF, CbzN 040 CF, CbzN 0 10 CF, Compound 42b Compound 42d Phosgene (6.67 mL, 12.4 mmol, 20% in toluene) was added dropwise to a vigorously stirred mixture of Compound 42b (1.5 g, 2.48 mmol) in CH2Cl2 (30 mL) and a saturated NaHCO3 solution (30 mL) at 0 C. The mixture was stirred at 0 C for 3 hours before it was diluted with CH2Cl2 (50 mL) and the aqueous phase was separated from the organic phase. The organic phase was washed with a cold aqueous NH4CI solution, brine, and dried over MgSO4. The solvent was reduced to a volume of about 5 mL under reduced pressure, at room temperature, to remove excess phosgene. The residue was dissolved in CH2C12 (15 mL) and treated with NH2NHC(0)H (0.446 g, 7.44 mmol) and pyridine (1.2 mL, 14.88 mmol) at room temperature. The resulting solution was stirred at room temperature for 12 hours. The reaction mixture was then diluted with Et0Ac (200 mL) and washed with HCI (50 mL, 0.5 N).
The aqueous phase was extracted with Et0Ac (3 x 30 mL). The combined organic layers were washed with brine (30 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using BIOTAGE
chromatography eluted with hexane/Et0Ac (v/v = 1/2 to 1/7) to give Compound 42d (1.1 g, 64%).
Step C:
HN-NHCHO N, \* NH
No4. NH CF, Nc CF
HMDS/TMSCl/Lil 0 CbzN RN 0 40 Compound 42d Compound 42 TMSCI (50 L) was added to a stirring mixture of Compound 42d (15 mg, 0.0217 mmol) and Lil (2.9 mg, 0.0217 mmol) in HMDS (0.5 mL) at room temp_eratur_e_Tbelesulting_reaction mixture_was_heated at_140 C-(bath temperature) for 30 hours before it was cooled down to room temperature.
The reaction mixture was diluted with Et0Ac (25 mL) and washed with HCI (5 mL, 1.0 N). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 6/4) to give Compound 42 (4 mg, 34%).

Alternatively, Compound 42 can also be prepared from Compound 23g as follows Step A:
cN..NH N, HNH cP

CF, CbzN
Dess-Martin periodinane CF, CbzN n CF

Compound 23g Compound 42e In a 10 mL round-bottomed flask, Compound 23g (0.02 g, 0.037 mmol, 1.0 equiv) was dissolved in DCM (3 mL) and the reaction mixture was cooled to 0 C. Dess-Martin periodinane (0.02 g, 0.048 mmol, 1.3 equiv) was added and the reaction mixture was stirred under nitrogen at room temperature for 45 minutes. The progress of the reaction was monitored by TLC (9/1 EtOAC/Me0H eluent), and the reaction was quenched after 1.5 hrs, by pouring the reaction mixture into separatory funnel containing saturated Na2S203/NaHCO3 solution (1:1) (5 mL). The mixture in the separatory funnel was shaken vigorously, and the aqueous layer was extracted with Et20 (2 x 5) and dried over MgSO4 and concentrated to give crude Compound 42e (0.02 g), which was used in the next step without further purification.
Step B:
N, H NH N.
CF, HO, CF, NH2OH.HCI, Na0Ac N =
CbzN 010 CF, Et0H CbzN
CF=
=
Compound 42f Compound 42g In a 25 mL round-bottomed flask, Compound 42f (0.09 g, 0.13 mmol, 1.0 equiv) and sodium acetate (0.032 g, 0.39 mmol, 3.0 equiv) were dissolved in Et0H (6 mL), to which hydroxylamine hydrochloride (0.056 g, 0.080 mmol, 6.0 equiv) was added. The reaction mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was then diluted with Et0Ac (15 mL), quenched with saturated NaHCO3 (5 mL), and the organic layer was washed using brine (5 mL) and dried over MgSO4 to give crude Compound 42g (0.95 g), which was used in the next step without further purification.
Step C:
N. N.
e NH c." NH
HON CF3 NC,õ CF, 1,1'-oxalyldiimidazole CbzN o CbzN
CF3 Benzene CF, Compound 42g Compound 42h In a 50 mL round-bottomed flask, Compound 42g (1.1 g, 0.59 mmol, 1.0equiv) was dissolved in benzene (25 mL). 1, 1'-oxalyldiimidazole (0.302 g, 1.89 mmol, 1.5 equiv) was added to the solution, and the reaction mixture was heated to 75 C under nitrogen for 4 hrs. The reaction mixture was then quenched with water (20 mL), diluted with Et0Ac (30 mL), dried over MgSO4 and concentrated to give a crude product. The crude product was purified using BIOTAGE chromatography (1/1 Et0Ac/hexanes) to give Compound 42h (0.7 g, 66% over three steps).
Step D:
N c"NH
NC, CF, No, N4 CF, CH,CN
CbzN 140/ ____________ HN 140 CF CF, Compound 42i Compound 42 In a 50 mL round-bottomed flask, Compound 42i (0.5 g, 0.742 mmol, 1.0 equiv) was taken up in acetonitrile (9 mL). The reaction mixture was cooled to 0 C, and TMSI (0.742 mL, 5.19 mmol, 7.0 equiv) was added dropwise via syringe. The reaction mixture was stirred overnight at room temperature. The progress of the reaction was monitored by MS, which indicated some starting material was still present. The reaction mixture was quenched using saturated Na2S203/NaHCO3 (1:1) (10 mL) and diluted with Et0Ac (20 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, and concentrated to yield a crude product. The crude product was purified using BIOTAGE chromatography (60/40 Et0Ac/hexanes) to give Compound 42 (0.4 g). HRMS calculated for C25H23F6N502 (M+H) 540.1834, found 540.1813.

N

Compound 43 Step A:
C):
H, HN NHBoc F30 N

Boc-aminocyclopropyl carboxylic acid n . CF
1-IN 0 0 IAN ,,,...
CF3 HAT!), EDC, DIEA
II *
Compound 44b Compound 43a Compound 43a was prepared by a procedure similar to the procedure for preparing Compound 28a.
Step B:
Fac c-.--;S> F3C
HN NHBoc HN NH2 TFA, DCM
HN ..,,z-n 3 HN /-* CF n 010 CF3 ..õ
* *
Compound 43a Compound 43b compound 04313 was prepared by a procedure similar to the procedure for preparing Compound 45c.
Step C:
F,C 0 HN NH, N CF, HC(OMe), n CF, CF, =
Compound 43c Compound 43 Compound 43 was prepared by a procedure similar to the procedure for preparing Compound 28 (step c).

N-N
1.10._},rt0 F,C
CF, Compound 44 Step A:

CF, CF, Zn, AcOH
HN HN

Compound 442 Compound 44b In a 50 mL round-bottomed flask, Compound 44a (1.1 g, 2.31 mmol, 1.0 equiv) was dissolved in acetic acid (20 mL), and the resulting reaction mixture was cooled to 0 C. Zn powder (1.51 g, 23.1 mmol, 10.0 equiv) was added and the mixture was refluxed for 2.5 hr. The reaction mixture was then filtered through CELITE, concentrated, diluted with Et0Ac (30 mL), and neutralized with saturated NaHCO3 (30 mL). The aqueous phase was extracted with Et0Ac (2 x 10 mL), washed with brine (20 mL), dried over MgSO4 and concentrated. The crude product was purified using a filter column to yield 1.0 g (99%) of Compound 44b.
Step B:

NHBoc B0cNHNH2, CD!

OF, THF CF3 Compound 44b Compound 44c Compound 44c was prepared by a procedure similar to the procedure for preparing Compound 45b.
Step C:
0 0 id_ )\--N'NHBoc HN H HN H

1. TFA, DCM
CF 2. Pyridine, DCM CF
BnOTh,CI çj Compound 44c Compound 44d Compound 44d was prepared by a procedure similar to the procedure for preparing Compound 45c.
Step 0 H 7-0Bn HN 11 0 Bno,,AN' CF3 2M No0H, Et0H F3C
HN . 0 40) HN 1411 Compound 44e Compound 44d =
=
Compound 44e was prepared by a procedure similar to the procedure for preparing Compound 45d.
Step E:

N-N N-N
HCI,)LN

Pd/C, HCO3NH4 010 CF3 MeOH/H20 HN 1110 Compound 44e Compound 44 In a 10 mL round-bottomed flask, Compound 44e (0.34 g, 0.54 mmol, 1.0 equiv) was taken up in 5.5 mL of Me0H/H20 (10:1). The round-bottomed flask was degassed, and Pd/C (10 wt%, 0.18 g) was added followed by HCO2NH4 (0.174 g, 2.68 mmol, 5.0 equiv). The resulting heterogeneous mixture was refluxed overnight, cooled, filtered through CELITE, concentrated, diluted with Et0Ac (10 mL), washed with saturated NaHCO3 (10 mL), and dried over Na2SO4. The crude product was purified by BIOTAGE
chromatography (9:1 Et0Ac:Me0H) to yield 0.11 g (38%) of Compound 44.
HRMS calculated for C25H26F6N403 (M+H) 545.1987, found 545.1988.
PREPARATIVE EXAMPLE 45 and 46 N-N N-14\
MeONO
Me0,..."(Nf Fig 0 41 CF3 CF, NI
Compound 45 Compound 46 Step A:

2 CF, CF3 Raney Ni, H2 _____________________________________________________________ C5214 0 CbzN

CR, _____________________________________ t0 CF, Compound 41a Compound 45a Compound 41a (2.8 g, 4.59 mmol, 1.0 equiv) was taken up in ethanol (15 mL). Raney nickel was added to the solution, and the reaction mixture was hydrogenated in a Parr shaker at 60 psi. The progress of the hydrogenation was monitored by TLC (4/1 Et0Ac/hexanes). After 3 hours, the reaction mixture was then filtered through CEL1TE, washed with ethanol (30 mL) and concentrated. The crude product was purified by BIOTAGE
chromatography (4/1 Et0Ac/hexanes), to give Compound 45a (1.75 g, 65%).
Step B:

, A NHBoc CF, CF3 CbzN o 40 CF, BocNHNH2, CD' _________________________________________________________ * CbzN ., o Compound 45a ' Compound 45b In a 50 mL round-bottomed flask, Compound 45a (1.0 g, 1.72 mmol, 1.0 equiv) was dissolved in dry THF (20 mL) and cooled to 0 C. A solution of ter-butyl carbazate (0.228 g, 1.72 mmol, 1.0 equiv) and carbonyl diimidazole (0.3359, 2.06 mmol, 1.2 equiv), which was previously stirred in dry THF (10 mL), was added to the above cooled solution via cannula. The reaction mixture was allowed to warm to room temperature and was stirred overnight.
The reaction mixture was then concentrated and purified by BIOTAGE
chromatography (1/1 Et0Ac/hexanes) to give Compound 45b (0.85 g, 67%).
Step C:
13\\ NHBoc HN)"--- H HN H
CF, N . 0 40 CF3c, 1. TFA, DCM
CbzN 2. Pyridine, DC M-Me0,,C1 CF, CbzN .. 0 0 CF, Compound 45b Compound 45c In a 50 mL round-bottomed flask, Compound 45b (0.39 g, 0.53 mmol, 1.0 equiv) was dissolved in CH2Cl2 (10.0 mL) and cooled to 0 C.
Trifluoroacetic acid (1.02 mL, 13.2 mmol, 25.0 equiv) was added to the solution, and the reaction mixture was allowed to stir at room temperature.
The progress of the reaction was monitored by MS (i.e., disappearance of starting material). The reaction mixture was concentrated after 7 h, and was used in the next step without any further purification. The crude intermediate was dissolved in THF (5 mL) and cooled to 0 C. A 20 % aqueous solution of NaOH (5.0 mL) was added, followed by methoxyacetyl chloride (0.096 mL, 1.06 mmol, 2.0 equiv). The reaction mixture was allowed to stir at room temperature overnight, and was then diluted with H20 (10 mL), extracted with Et20 (2 x 10 mL), washed with brine (10 mL), dried over MgSO4 and concentrated to yield crude Compound 45c (0.35 g, 95%), which was used in the next step without any further purification.
Step D:
0>\__NyrOMe CF, 2 M NaOH, Et0H F,C
CbzN
CF, CbzN , 0 411 CF, Compound 45c Compound 45d In a 25 mL round-bottomed flask, Compound 45c (0.35 g, 0.49 mmol, 1.0 equiv) was dissolved in Et0H (3.0 mL). 3.0 mL of a 6 M solution of NaOH
was added and the reaction mixture was refluxed overnight. The reaction mixture was then concentrated and purified by preparative TLC (Et0Ac) to give 0.145 g (42%) of Compound 45d.
Step E:
Me0,}1, >= Me0,74-W
F,C F,C F,C
H,, Pd(OH)2 *
CbzN ., 0 411 HN HH 411 CF, Me0H CF, CF, Compound 45d Compound 45 Compound 46 In a 10 mL round-bottomed flask, Compound 45d (0.125 g, 0.18 mmol, 1.0 equiv) was dissolved in 3 mL Me0H. Pd(OH)2 (0.010 g, 0.072 mmol, 40 wt%) was added, and the heterogeneous mixture was hydrogenated at room temperature. The progress of the hydrogenation was monitored by MS. The reaction mixture was filtered through CELITE, concentrated and purified by preparative TLC (Et0Ac) affording a mixture of Compounds 45 and 46 (0.008 g, 8%). HRMS calculated for C26H28F6N403 (M+H) 559.2144, found 559.2146.
PREPARATIVE EXAMPLE 47 and 48 H H
,,, N
N'N
rii__.(3 :A: (--) MeO,SHN N CF, Me02SHN Ni CF, ,,,,0 or CF, CF, Compound 47 Compound 48 Step A:
H H
:,,C. 0 H,N N CF, MeO,SHN N CF3 ,,,,,o 40 CF, CF, Compound 49 Compound 47 Msa, TEA
+
+
H
H -N
N"N ,N.L 0 Me02SHN N.; CF, H2N N: CF, .g ?
CF, 0 0 CF, Compound 50 . Compound 48 In a 10 mL round-bottomed flask, a mixture of Compounds 49 and 50 (0.025 g, 0.047 mmol, 1.0 equiv) was dissolved in 2 mL of DCM and cooled to 0 C. Triethylamine (0.0073 mL, 0.052 mmol, 1.1 equiv) was added, followed by MeS02C1 (0.004 mL, 0.052 mmol, 1.1 equiv). The reaction mixture was allowed to stir overnight. The reaction mixture was then diluted with Et0Ac (10 mL) and quenched with saturated Na(-1CO3 (5 mL). The aqueous phase was extracted with Et0Ac (2 x 5 mL), dried over Na2SO4, and concentrated.
The crude product was purified by preparative TLC (4:1 Et0Adhexanes) to give 0.028 g (100%) of a mixture of Compounds 47 and 48. HRMS
calculated for C25H27F6N504S (M+H) 608.1766, found 608.1785.
PREPARATIVE EXAMPLE 49 and 50 H H
N'N N'N
.L. o )I--N
H2N) N CF3 .(= r H2N .3 CF3 .,3 Compound 49 Compound 50 Step A:
H H
N"N N'N

HNO, Cbz .,N 0 02N-CbzN , 0 .

Compound 49a Compound 49b Compound 49a (0.50 g, 0.77 mmol, 1.0 equiv) was added to a 50 mL
round-bottomed flask. Fuming HNO3 (3 mL) was then added to the flask, and the resulting reaction mixture was allowed to stand for 1 h. After the reaction was complete, ice (10 g) was added. The reaction mixture was diluted with Et0Ac (25 mL) and neutralized with saturated NaOH (3 mL). The aqueous phase was extracted with Et0Ac (2 x 10 mL). The organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated. The crude product was purified by BlOTAGE Chromatography (7:3 Et0Ac:hexanes) to give 0.45 g (79%) of Compound 49b.
Step B:

N H H
N-N
..0 02V¨N CF, H2N1 N CF3 H2N Ft CF3 02N-CbzN 0 0 CF3 Zn, AcOH ,- HN ,õ,c) I. + HN .,,,o 40 Compound 49b Compound 49 Compound 50 Compounds 49 and 50 were prepared by a procedure similar to the procedure for preparing Compound 44b. HRMS calculated for C24H25F6N502 (M+H) 530.1991, found 530.1977.

N, Htsl'N'l 0 HN\' -4`1 --0/ CF, ----t4 =='---NH2 CF, 0 NH3/Me0H
CbzN .. 0 I. 80 C CbzN = 40 40 ' CF, 40 '',C) CF, 55 51a Compound 55 (0.078 g, 0.11 mmol, 1.0 equiv) was dissolved in 7 M
ammonia in Me0H (3.0 mL) and was added to a small Parr bomb, which was heated to 80 C for 2 days. The progress of the reaction was monitored by TLC (9/1 CH2Cl2/Me0H). Upon completion of the reaction, the reaction mixture was concentrated to give a crude product in the form of a white solid.

The crude product was purified using BIOTAGE chromatography (2:1 to 4:1 Et0Ac/Hexane) to give Compound 51a as a white solid (0.48 g).
Electrospray MS [M+1] 692.2.
N.õ
1-IN'N-7 0,\ FIN' /---N .--NH2 CF, ---N .=,'''---NH2 10%Pd/C, NF1,02CH 0 CbzN .. 0 40 Me0H . FIN 0 40 0 ''' CF, 5 ' CF, 51a Compound 51 Compound 51a (0.045 g, 0.065 mmol, 1.0 equiv.) was dissolved in dry Me0H (2.0 mL) and was treated with 10% Pd/C (40% wt.) followed by ammonium formate (0.02g, 0.03 mmol, 5.0 equiv.) under an inert atmosphere.
The reaction mixture was heated to reflux and the progress of the reaction was monitored by TLC (100% Et0Ac). The reaction was completed in 1 hr.
The reaction mixture was filtered through CELITE, washed with Et0Ac and concentrated under vacuum. The resulting residue was taken up in Et0Ac, washed with saturated NaHCO3, followed by brine and H20 to give the desired product, Compound 51 in the form of a white solid, which was converted to its HCI salt (0.034g, 94%).
HRMS (FAB) calculated for C26H28F6N302 (M+1)558.19242, found 558.19398.

NH

'= 0 HN

Compound 52 Step A:
N, t NH
e'NH
o CF3 H3CO, j = 0 CF
NH,OCH,, MOH 0 HN is CF3 HN n OF, Compound 53 Compound 52 Compound 53 (18.1 mg, 0.0325 mmol) in Et0H (2.5 mL) was treated with MeONH2.HCI (24.4 mg, 0.292 mmol) and Na0Ac (12.0 mg, 0.146 mmol) at room temperature. The reaction mixture was stirred at 60 C for 12 hr, then diluted with Et0Ac (20 mL) and washed with aqueous NaHCO3. The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After fiVation and concentration, the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 1/1 to 1/9) to give Compound 52 (16 mg, 84%).
Electrospray MS [M4-1] 586.1.

NA CF, HN cF
41.
Compound 53 Step A:
N, NH
,NH
HO o CFs a. Dess-Martin periodinane CF3 b. MeMgBr, THF
CbzN 40 Dess-Martin periodinane CF, _______________________________________ ¨ CbzN n = CF3 Compound 23h Compound 53a Dess-Martin period inane (0.234 g, 0.553 mmol) was added to a mixture of Compound 23h (0.25 g, 0.369 mmol) and NaHCO3 (0.232 g, 2.76 mmol) in CH2Cl2 (5.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with Et0Ac (50 mL) and water (10 mL). The organic phase was washed with saturated Na2S203 solution (3x15 mL). The combined aqueous phases were extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude aldehyde (0.25 g) was taken up in anhydrous THF (4.0 mL) and was treated with MeMgBr (0.49 mL, 1.48 mmol, 3.0 M in Et20) at -78 C. The reaction temperature was slowly increased to room temperature and the reaction was quenched in 2 hours with the slow addition of saturated aqueous NR4Clsolution (10 mL). The reaction mixture was then diluted with Et0Ac (50 mL) and neutralized with 0.5 N HCI until the aqueous phase was slightly = -128-acidic. The aqueous phase was extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude secondary alcohol (0.26 g) was taken up in CH2Cl2 (5.0 mL) and treated with Dess-Martin period inane (0.468 g, 1.11 mmol) and NaHCO3 (0.466 g, 6.55 mmol) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with Et0Ac (50 mL) and water (10 mL). The organic phase was washed with saturated Na2S203 solution (3x15 mL). The combined aqueous phases were extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude produce was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v = 1/1) to give Compound 53a (0.11g, 43% for 3 steps).
Step B:
N.jNH N, N--kCF3 N--kNH
0 H2, Pd(OH)3!C, L/C, Et0H b CbzN 40 Compound 53a Compound 53 Compound 53a (107 mg, 0.155 mmol) in Et0H (5.0 mL) was treated at room temperature with Pd(OH)2/C (21.5 mg, 10 wt%) and was hydrogenated with a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Et0H
(15 mL). The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v =
1/3 to 1/9) to give Compound 53 (66 mg, 76%). Electrospray MS fm+ir 557.3.

e-NH
HO ,N4 cF3 HN
CF, Compound 54 N, QN
pH
CF, HON,PH
NH,OH, Et0H N o CF, HN = C F3 " CF

Compound 53 Compound 54 Compound 53 (14.3 mg, 0.0257 mmol) in Et0H (2.5 mL) was treated with HONH2.HCI (10.7 mg, 0.154 mmol) and Na0Ac (6.3 mg, 0.077 mmol) at room temperature. The reaction mixture was stirred at 60 C for 12 hr, then diluted with Et0Ac (20 mL) and washed with aqueous NaHCO3. The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 1/2) to give Compound 54 (11 mg, 75%).
Electrospray MS [M+1] 572.1.

0N,NH

CF, Compound 55 Step A:

N, NH c'N,NH
cF3 ab: 2D-emSeSZal-rt2I-nbuPteerniediNnaang02 H3C0-11, N40 CF, NaH2PO4, tert-butanol CbzN 411 C. TMSCHN2, Me0H, Phi-1 CbzN 40, CF, _______________________________________________________ CF, Compound 23h Compound 55a Dess-Martin Periodinane (0.12 g, 0.284 mmol) was added to a mixture of Compound 23h (96.3 mg, 0.142 mmol) and NaHCO3 (0.12 g, 1.42 mmol) in CH2C12 (3.0 mL) at room temperature. The reaction mixture was stirred for 1 hour before it was diluted with addition of Et0Ac (50 mL) and water (10 mL).
The organic phase was washed with saturated Na2S203 solution (3x15 mL).
The combined aqueous phases were extracted with Et0Ac (3 x 15 mL). The combined organic layers were washed with NaOH solution (15 mL, 1.0 N), water (10 mL), brine (15 mL), and dried over MgSO4. After filtration and concentration, the crude aldehyde (96.3 mg) was taken up in tert-butanol (2.0 mL) and water (0.5 mL) and treated with NaH2PO4-1-120 (39.2 mg, 0.284 mmol), NaC102 (44.9 mg, 0.497 mmol) and 2-methyl-2-butene (0.105 mL, 0.994 mmol) successively. The reaction mixture was stirred for 2 hours and then diluted with Et0Ac (20 mL) and washed with aqueous NH4CI. The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4.
After filtration and concentration, the crude acid (95 mg) was dissolved in benzene (2.8 mL) and Me0H (0.7 mL). The resulting solution was treated with TMSCHN2 (82.24, 0.164 mmol) at room temperature and stirred for 20 minutes. The solvent was removed under reduced pressure and the crude product was purified using BIOTAGE chromatography (hexane/Et0Ac, v/v =
2/3) to give Compound 55a (70 mg, 35% for 3 steps).
Step B:
0 NH0 c?..N,NH
H3C0-11,.. CF, H,, Pd(OH)2/C, Et0H n3C0 = 0 CF3 CbzN0 410 CF, OF, Compound 55a Compound 55 Compound 55a (38 mg, 0.0537 mmol) in Et0H (3.0 mL) was treated at room temperature with Pd(OH)2/C (7.6 mg, 10 wt%) and was hydrogenated with a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). The solvent was removed under reduced pressure and the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 2/3) to give Compound 55 (24 mg, 78%). Electrospray MS [M+1]+ 573.1.

Compound 56 Step A:
co-IN;N NH

CF, CF, a. H3, Pd(OH)2/C, Et0H
b. HCI, Etp CbzN 40 HN

Compound 56a Compound 56 Compound 56a (15 mg, 0.0227 mmol) in Et0H (2.0 mL) was treated at room temperature with Pd(OH)21C (3.6 mg, 10 wt%) and was hydrogenated with a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Et0H (15 mL). The solvent was removed under reduced pressure and the crude product was taken up in Et20 (0.5 mL) and treated with HCI in ether (0.23 mL, 0.23 mmol, 1.0 M in ether). The mixture was stirred at room temperature for 12 hours.
The mixture was then diluted with Et0Ac (20 mL) and washed with aqueous NaOH (5 mL, 0.5 N). The aqueous phase was extracted with Et0Ac (3 x 10 mL), The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4. After filtration and concentration, the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 1/1) to give Compound 56 (8.5 mg, 67%). Electrospray MS [M-1-1]+ 563.1.

N.,NH
H3Cõ. CF, HN
CF, Compound 57 Step A:
fN,NH
N
HO¨%. CF, N
a. MsCI, NEt3, CH2Cl2 H,C, CF, CF, CbzN 40 u3 b. NaBH., DMF, 90 C 0 CbzN .F, CbzN
=
= CF, Compound 23h Compound 57a Compound 56a MSCI (11.74, 0.151 mmol) was added to a solution of Compound 23h (42.8 mg, 0.063 mmol) and Et3N (26.4 !IL, 0.189 mmol) in CH2Cl2 (1.0 mL) at room temperature. The reaction mixture was quenched with water (5.0 mL) after 30 minutes and diluted with CH2Cl2 (15 mL). The aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (19 mL), and dried over MgSO4. After filtration and concentration, the crude mesylate (44 mg, 0.0582 mmol) was taken up in anhydrous DMF (2.0 mL) and treated with NaBF14 (11.0 mg, 0.291 mmol). The reaction mixture was heated at 90 C for 1 hour before it was cooled down to room temperature. The reaction mixture was then diluted with Et0Ac (20 mL) and washed with aqueous HCI (5 mL, 1.0 M). The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (3x10 mL), brine (10 mL), and dried over MgSO4.
After filtration and concentration, the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 3/2) to give Compound 57a (18 mg, 43%) and Compound 56a (15 mg, 36%).
Step B:
N,NHN,NH
CF3 H3C,õ NA0 CF
H2, Pd(OH)21C, Et0H
CbzN

Compound 57a Compound 57 Compound 57a (18 mg, 0.027 mmol) in Et0H (3.0 mL) was treated at room temperature with Pd(OH)2/C (3.6 mg, 10 wt%) and was hydrogenated with a H2 balloon for 30 minutes. The reaction solution was filtered through a short pad of CELITE and the residue was washed with EtOH (15 mL). The solvent was removed under reduced pressure and the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 1/1) to give Compound 57 (10 mg, 70%). Electrospray MS [M+1] 529.1.

N,NH
H CO

Compound 58 N.
cN'NH
CF3 H,CO, NH2OCH3, Et0H N = \O CF3 CF, Compound 19 Compound 58 Compound 19 (10.0 mg, 0.0175 mmol) in Et0H (1.5 mL) was treated with MeONH2=HCI (14.6 mg, 0.175 mmol) and Na0Ac (7.2 mg, 0.0876 mmol) at room temperature. The reaction mixture was stirred at 60 C for 12 hr, and was then diluted with Et0Ac (20 mL) and washed with aqueous NaHCO3. The aqueous phase was extracted with Et0Ac (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over MgSO4.
After filtration and concentration, the crude product was purified using preparative TLC (hexane/Et0Ac, v/v = 2/3) to give Compound 58 (10.5 mg, 100%). Electrospray MS [M+1] 600.1.

HN
CF, Compound 59 Step A:
en0 NH' CF, NHAc 13n0 CF3 AcCI, Et3N, CI-13C13 CbzN 40 CF, ____________________________________________ CbzN
CF
Compound 59a Compound 59b To a solution of Compound 59a (0.53 g, 0.76 mmol) in CH2Cl2 (4 mL) was added Et3N (0.14 mL, 0.98 mmol). The reaction mixture was cooled to -78 C and acetyl chloride (0.065 mL, 0.91 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 72 hours.
Additional Et3N (0.068 mL) and acetyl chloride (0.033 mL) was added to the reaction mixture, which was then stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified with BIOTAGE
chromatography (hexane/Et0Ac, v/v = 3/2) to give Compound 59b (0.5 g).
Step B:

NHAc NHAc 8n0 CF, HO CF, BC13, CH2C12, -78 C
CbzN 40 CbzN Si CF, CF, Compound59b Compound 59c BCI3 (3.7 mL, 3.7 mmol, 1.0 M in hexane) was added dropwise to a stirring solution of Compound 59b (0.55 g, 0.74 mmol) in CH2Cl2 (9 mL) at -78 C. The reaction was quenched in 1 hour by the addition of aqueous NaHCO3 solution (50 mL) at -78 C. The reaction mixture was diluted with Et0Ac (200 mL) and washed with saturated aqueous NaHCO3 (100 mL), and dried over Na2SO4. The mixture was filtered and concentrated to give crude Compound 59c (0.4 g), which was used in the next reaction without further purification.
Step C:
NHAc NHAc HO CF, 0 CF, Dess-Marlin, NaHCO3, CH2Cl2 CbzN CbzN
CF, CF, lit Compound 59c Compound 59d Dess-Martin periodinane (0.12 g, 0.28 mmol) was added to a mixture of Compound 59c (0.12 g, 0.18 mmol) and NaHCO3 (0.17 g, 2.0 mmol) in CH2Cl2 (5.0 mL) at room temperature and stirred for 45 minutes. Additional Dess-Martin periodinane (50 mg) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was then concentrated and purified with BIOTAGE chromatography (hexane/Et0Ac, v/v = 1/1) to give Compound 59d (0.1 g).
Step D:

P I NHAc NHAc CF3 0 CF, TosCH,NC, K,CO3, Me0H
CbzN 40 CbzN

Compound 69d Compound 59e A mixture of Compound 59d (0.11 g, 0.17 mmol), potassium bicarbonate (26 mg, 0.19 mmol), tosylmethyl isocyanide (36 mg, 0.19 mmol) and methanol (3 mL) was heated at 80 C for 48 hours. The reaction mixture was then concentrated and diluted with Et0Ac (200 mL) and washed with saturated aqueous NaHCO3 (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified with B1OTAGE chromatography (hexane/Et0Ac, v/v = 2/3 to 0/100) to give Compound 59e (50 mg).
Step E:
/
0 NHAc 0 õ NHAc CF, CF, CbzN H2,Pd(OH)21C, Me0H HN
=

Compound 59d Compound 59 Compound 59d (0.31 mg, 0.45 mmol) in Me0H (10.0 mL) was treated at room temperature with Pd(OH)2/C (0.2 g, 20 wt%) and was hydrogenated with a H2 balloon for 2 hours. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Me0H (30 mL). The solvent was removed under reduced pressure and the crude product was purified with BIOTAGE chromatography (Et0Ac/Me0H, v/v = 911) to give mixture of two isomers (190 mg), which were further purified by HPLC (chiral OD column) with hexane/IPA (v/v = 9/1) to give Compound 59 (90 mg).

-N
HN
0N' CF, HN
CF, Compound 60 Step A:
HO,C HN
CF, a. CICO,Et, Et,N, CH,CI, 0 CF, b, NaN,, Bu4NHE04 CbzN
CF, C13zN
c.õ-msN3, toluene, 110 00 CF, =
Compound 60a Compound 60b To a solution of Compound 60a (0.26 g, 0.43 mmol) in CH2Cl2 (4 mL) at 0 C was added Et3N (0.071 mL, 0.51 mmol) followed by ethylchloroformate (0.052 mL, 0.56 mmol), and the reaction mixture was stirred for 1 hour. To the reaction mixture was then added sodium azide (64 mg, 0.98 mmol) and tetrabutylammonium hydrogen sulfate (43 mg, 0.13 mmol) and stirring was continued for 1 hour. The reaction mixture was then diluted with CH2Cl2 (100 ml) and washed with water (1 x 100 mL) and brine (1 x 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in dry toluene (4 ml) and heated to 80 C for 2 hours and then cooled to room temperature. TMSN3 (0.13 mL, 0.94 mmol) was added and the reaction mixture was heated to -110 C for 18 hours. The reaction mixture was then cooled to room temperature, concentrated and purified by BIOTAGE
chromatography (hexane/Et0Ac, v/v = 2/1, followed by Me0H/Et0Ac, v/v =
1/99) to give Compound 60b (0.17 g).
Step B:

-N
HN
HN
0 CF, QNCF, Pd(OH)C, Me0H
CbzN HN
CF, CF, Compound 60b Compound 60 Compound 60b (0.17 mg, 0.26 mmol) in Me0H (10.0 mL) was treated at room temperature with Pd(OH)2/C (15 mg, 20 wt%) and was hydrogenated with a H2 balloon for 2 hours. The reaction solution was filtered through a short pad of CELITE and the residue was washed with Me0H (30 mt.). The solvent was removed under reduced pressure and the crude product was purified by BIOTAGE chromatography (Et0Ac/Me0H, v/v = 98/2) to give Compound 60 (20 mg).
The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

Claims (47)

1. A compound of formula I:
or pharmaceutically acceptable salts and/or solvates or hydrates thereof, wherein:
R1 and R2 are each independently selected from the group consisting of C1-20 alkyl, C1-20 haloalkyl, C1-20 alkyl substituted with one or more hydroxyl groups, -CN, C2-15 alkynyl, -N(R6)2, N(R6)-S(O2)-C1-20 alkyl, -N(R6)-C(O)-N(R9)2, -C1-20 alkylene-CN, -C3-10 cycloalkylene-CN, -C1-20 alkylene-O-C1-20 alkyl, -C(O)-C1-20 alkyl, -C(=N-OR5)-C1-20 alkyl, -C(O)-N(R9)2, -C(O)-O- C1-20 alkyl, -C1-20 alkylene-C(O)-C1-20 alkyl, -C1-20 alkylene-C(O)-O-C1-20 alkyl, -C1-20 alkylene-C(O)-N(R9)2, wherein at least one of R1 and R2 is -CN, <MG>
W iS =C(R8)- or =N-;
X-Y is -C(O)-CH2-, -C(O)-O-, -C(O)-N(R6)-C(O)-, -S(O2)-CH2- or -S(O2)-N(R6)-C(O)-;
Z is ¨C(R7)2-, -N(R6)-, or -O-;
R3 is selected from the group consisting of H, -CH2OR8 and C1-20 alkyl;

R4 is selected from the group consisting of H, C1-20 alkyl, C3-10 cycloalkyl, heterocycloalkyl selected from the group consisting of piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl or azetidinyl, heteroaryl selected from the group consisting of pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl, tetrazolyl, tetrahydroisoquinolyl and tetrahydroquinolyl, C6-14 aryl, H-C(O)-, C1-20 alkyl-C(O)-, C3-10 cycloalkyl-C(O)-, C6-14 aryl-C(O)-, C1-20 alkylsulfonyl, and C6-14 arylsulfonyl;
R5 is H or C1-20 alkyl;
R6 is selected from the group consisting of H, C1-20 alkyl, C3-10 cycloalkyl, and C6-14 aryl;
each R7 is independently H or C1-20 alkyl; or each R7, together with the ring carbon to which they are shown attached, form a C3-10 cycloalkylene ring;
R8 is selected from the group consisting of H, C1-20 alkyl, C1-20 alkyl substituted with one or more hydroxyl groups, -N(R6)2, -N(R6)-S(O2)-C1-20 alkyl, N(R6)-S(O2)-C6-14 aryl-, -N(R6)-C(O)-C1-20 alkyl, -N(R6)-C(O)-05-14 aryl, C1-20 alkylene-O-C1-20 alkyl, and -CN;
R9 is selected from the group consisting of H, C1-20 alkyl and C6-14 aryl, or each R9, together with the nitrogen to which they are shown attached, form a heterocycloalkyl selected from the group consisting of Ar1 and Ar2 are each independently selected from the group consisting of unsubstituted phenyl and phenyl substituted with 0-3 substituents selected from the group consisting of halogen, C1-20 alkyl, alkoxy, halo C1-20 alkyl, haloalkoxy, -CN, -OH, and -NO2;

n is 0, 1 or 2; and m is 1, 2 or 3.
2. The compound according to Claim 1, wherein the compound of Formula I has the following structure:
3. The compound according to Claim 1, wherein:
R3 is C1-20alkyl;
R4 is H;
Ar1 is substituted or unsubstituted phenyl;
Ar2 is substituted or unsubstituted phenyl; and n is 1.
4. The compound according to Claim 2, wherein:
R3 is C1-20alkyl;
R4 is H;
Ar1 is unsubstituted phenyl;
Ar2 is substituted phenyl; and n is 1.
5. The compound according to Claim 1, wherein:
R3 is C1-20alkyl;
R4 is H;
Ar1 is monosubstituted phenyl;
Ar2 is substituted phenyl; and n is 1.
6. The compound according to Claim 4, wherein:
Ar2 is 3,5-bis(trifluoromethyl)phenyl, 3,5-bis(fluoro)phenyl, 3,5-bis(chloro)phenyl, 3,5-bis(methyl)phenyl, or 3,5-bis(methoxy)phenyl.
7. The compound according to Claim 6, wherein:
R3 is -CH3.
8. The compound according to claim 7, wherein:
one of R1 or R2 is
9. The compound according to claim 7, wherein:
one of R1 or R2 is
10. The compound according to claim 7, wherein:
one of R1 or R2 is
11. The compound according to claim 7, wherein:
one of R1 or R2 is -CN.
12. The compound according to claim 8, wherein:
X is -S(O2)-;
Y is -CH2-; and m is 2.
13. The compound according to claim 8, wherein:
X is -C(O)-;
Y is -CH2-; and m is 2.
14. The compound according to claim 8, wherein:
X is -C(O)-;
Y is -CH2-; and m is 3.
15. The compound according to claim 8, wherein:
X is -O(O)-;
Y is -O-; and m is 2.
16. The compound according to claim 8, wherein:
X is -C(O)-;
Y is -CH2-: and m is 1.
17. The compound according to claim 8, wherein:
X is -C(O)-;
Y is -NH-C(O)-; and m is 1.
18. The compound according to claim 9, wherein:
Z is -NH-; and R8 is H.
19. The compound according to claim 9, wherein:
Z is -NH-; and R8 is -NH-S(O2)-CH3.
20. The compound according to claim 9, wherein:
Z is -NH-; and R8 is -CH2-OH.
21. The compound according to claim 9, wherein:
Z is -NH-; and R8 is -CH2-O-CH3.
22. The compound according to claim 9, wherein:
Z is -NH-; and R8 is -NH2.
23. The compound according to claim 9, wherein:
Z is and R8 is H.
24. The compound according to claim 9, wherein:
Z is -C(CH3)2-; and R8 is H.
25. The compound according to claim 1 having the Formula 1B
wherein R1 and R2 are selected from the group consisting of:
26. A compound according to claim 1 represented by the following formula:
27. A compound according to claim 1 represented by the following formula:
28. A compound according to claim 1 represented by the following formula:
29. A compound according to claim 1 represented by the following formula:
30. A compound according to claim 1 represented by the following formula:
31. A compound according to claim 1 represented by the following formula:
32. A compound according to claim 1 represented by the following formula:
33. A compound according to claim 1 represented by the following formula:
34. A compound according to claim 1 represented by the following formula.
35. A pharmaceutical composition comprising:
at least one compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable carrier.
36. The pharmaceutical composition of claim 35 further comprising at least one serotonin reuptake inhibitor.
37. Use of an effective amount of at least one compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt and/or solvate or hydrate thereof for treating a physiological disorder, symptom or disease, wherein the physiological disorder, symptom or disease is selected from the group consisting of respiratory diseases, inflammatory diseases, skin disorders, ophthalmological disorders, central nervous system conditions, depression, anxiety, phobia, bipolar disorder, additions, alcohol dependence, psychoactive substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDS related dementia, Towne's disease, stress related disorders, obsessive/compulsive disorders, eating disorders, bulimia, anorexia nervosa, binge eating, sleep disorders, mania, premenstrual syndrome, gastrointestinal disorders, atherosclerosis, fibrosing disorders, obesity, Type II diabetes, pain related disorders, headache, neuropathic pain, postoperative pain, chronic pain syndrome, bladder disorders, genitourinary disorders, cough, emesis and nausea.
38. The use of claim 37, wherein the physiological disorder, symptom or disease is emesis, depression, anxiety or cough.
39. The use of claim 37, wherein the physiological disorder, symptom or disease is depression or anxiety.
40. The use of claim 37, wherein the physiological disorder, symptom or disease is emesis and/or nausea.
41. The use of claim 38, wherein the physiological disorder, symptom or disease is cough.
42. The use of claim 39, in combination with an effective amount of at least one anti-depressant agent and/or at least one anti-anxiety agent.
43. The use of claim 39, in combination with:
an effective amount of at least one selective serotonin reuptake inhibitor, and wherein the physiological disorder, symptom or disease is depression.
44. Use of an effective amount of at least one compound of any one of claims 1 to 34 or a pharmaceutically acceptable salt and/or solvate or hydrate thereof for antagonizing an effect of a Substance P at a neurokinin-1 receptor site or for blocking at least one neurokinin-1 receptor, in a patient in need thereof.
45. The use according to claim 37 in combination with:
an effective amount of at least one active ingredient selected from the group consisting of other NK-1 receptor antagonists, selective serotonin reuptake inhibitors, dopamine receptor antagonists, serotonin 5-HT3 receptor antagonists, serotonin 5-HT2 receptor antagonists, nociceptin receptor antagonists, glucocorticoids and inhibitors of multidrug resistant protein 5; and wherein the physiological disorder, symptom or disease is selected from the group consisting of: a respiratory disease, depression, anxiety, phobia, bipolar disorder, alcohol dependence, psychoactive substance abuse, nociception, psychosis, schizophrenia, stress related disorder, obsessive/compulsive disorder, bulimia, anorexia nervosa, binge eating, sleep disorder, mania, premenstrual syndrome, gastrointestinal disorder, obesity, headache, neuropathic pain, post-operative pain, chronic pain syndrome, bladder disorder, genitourinary disorder, cough, emesis and nausea.
46. Use of an effective amount of at least one compound according any one of claims 1 to 34 or a pharmaceutically acceptable salt and/or solvate or hydrate thereof in combination with an effective amount of at least one serotonin 5-HT3 receptor antagonist and/or at least one glucocorticoid for treating emesis and/or nausea in a patient in need of such treatment.
47. The use of claim 46, wherein the serotonin 5-HT3 receptor antagonist is ondansetron and the glucocorticoid is dexamethasone.
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